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Lei Y, Cai S, Zhang JK, Ding SQ, Zhang ZH, Zhang CD, Dai DQ, Li YS. The role and mechanism of fatty acid oxidation in cancer drug resistance. Cell Death Discov 2025; 11:277. [PMID: 40514365 DOI: 10.1038/s41420-025-02554-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 05/06/2025] [Accepted: 05/30/2025] [Indexed: 06/16/2025] Open
Abstract
Cancer is a leading cause of death globally. While drug treatment is the most commonly used method for cancer therapy, it is often hampered by drug resistance. Consequently, the mechanisms of drug resistance in cancer therapy have become a focus of current research. The mechanisms underlying cancer drug resistance are complex and may involve genetic mutation, immune escape, and metabolic reprogramming, amongst others. Metabolic reprogramming is an important marker of tumor cells, and an increasing number of studies have shown that cancer drug resistance is correlated with metabolic reprogramming, especially when fatty acid oxidation (FAO) is involved. More importantly, many preclinical studies have shown that when anti-tumor drugs are combined with FAO inhibitors, cancer cell resistance to drugs can be reversed and the effectiveness of tumor therapy is enhanced. This review provides a comprehensive overview of the mechanisms by which FAO leads to cancer resistance as well as potential targets for inhibition of FAO.
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Affiliation(s)
- Yun Lei
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Shuang Cai
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Jia-Kui Zhang
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Si-Qi Ding
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Zhan-He Zhang
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Chun-Dong Zhang
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
| | - Dong-Qiu Dai
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
- Cancer Center, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
| | - Yong-Shuang Li
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
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2
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Wang L, Wang Y, Ding K, Li Z, Zhang Z, Li X, Song Y, Xie L, Chen Z. YTHDC1 promotes postnatal brown adipose tissue development and thermogenesis by stabilizing PPARγ. EMBO J 2025; 44:3360-3380. [PMID: 40355558 DOI: 10.1038/s44318-025-00460-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 04/17/2025] [Accepted: 04/22/2025] [Indexed: 05/14/2025] Open
Abstract
Brown adipose tissue (BAT) plays a vital role in non-shivering thermogenesis and energy metabolism and is influenced by factors like environmental temperature, ageing, and obesity. However, the molecular mechanisms behind BAT development and thermogenesis are not fully understood. Our study identifies the m6A reader protein YTHDC1 as a crucial regulator of postnatal interscapular BAT development and energy metabolism in mice. YTHDC1 directly interacts with PPARγ through its intrinsically disordered region (IDR), thus protecting PPARγ from binding the E3 ubiquitin ligase ARIH2, and preventing its ubiquitin-mediated proteasomal degradation. Specifically, the ARIH2 RING2 domain is essential for PPARγ degradation, while PPARγ's A/B domain is necessary for their interaction. Deletion of Ythdc1 in BAT increases PPARγ degradation, impairing interscapular BAT development, thermogenesis, and overall energy expenditure. These findings reveal a novel mechanism by which YTHDC1 regulates BAT development and energy homeostasis independently of its m6A recognition function.
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Affiliation(s)
- Lihua Wang
- HIT Center for Life Sciences, School of Life Science and Technology, State Key Laboratory of Matter Behaviors in Space Environment, Frontier Science Center for Interaction between Space Environment and Matter, Zhengzhou Research Institute, Harbin Institute of Technology, Harbin, 150001, China
| | - Yuqin Wang
- HIT Center for Life Sciences, School of Life Science and Technology, State Key Laboratory of Matter Behaviors in Space Environment, Frontier Science Center for Interaction between Space Environment and Matter, Zhengzhou Research Institute, Harbin Institute of Technology, Harbin, 150001, China
- Department of Cardiovascular Surgery, Institute for Chronic Diseases, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Kaixin Ding
- HIT Center for Life Sciences, School of Life Science and Technology, State Key Laboratory of Matter Behaviors in Space Environment, Frontier Science Center for Interaction between Space Environment and Matter, Zhengzhou Research Institute, Harbin Institute of Technology, Harbin, 150001, China
| | - Zhenzhi Li
- HIT Center for Life Sciences, School of Life Science and Technology, State Key Laboratory of Matter Behaviors in Space Environment, Frontier Science Center for Interaction between Space Environment and Matter, Zhengzhou Research Institute, Harbin Institute of Technology, Harbin, 150001, China
| | - Zhipeng Zhang
- HIT Center for Life Sciences, School of Life Science and Technology, State Key Laboratory of Matter Behaviors in Space Environment, Frontier Science Center for Interaction between Space Environment and Matter, Zhengzhou Research Institute, Harbin Institute of Technology, Harbin, 150001, China
| | - Xinzhi Li
- NHC Key Laboratory of Cell Transplantation, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yue Song
- HIT Center for Life Sciences, School of Life Science and Technology, State Key Laboratory of Matter Behaviors in Space Environment, Frontier Science Center for Interaction between Space Environment and Matter, Zhengzhou Research Institute, Harbin Institute of Technology, Harbin, 150001, China
| | - Liwei Xie
- Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070, China
| | - Zheng Chen
- HIT Center for Life Sciences, School of Life Science and Technology, State Key Laboratory of Matter Behaviors in Space Environment, Frontier Science Center for Interaction between Space Environment and Matter, Zhengzhou Research Institute, Harbin Institute of Technology, Harbin, 150001, China.
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Fabiola León-Galván M, Medina-Rojas DS. DPP-IV and FAS inhibitory peptides: therapeutic alternative against diabesity. J Diabetes Metab Disord 2025; 24:100. [PMID: 40224529 PMCID: PMC11985882 DOI: 10.1007/s40200-025-01613-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/21/2025] [Indexed: 04/15/2025]
Abstract
Diabesity is a modern epidemic that indicates a strong association between obesity and diabetes. Key enzymes have been identified in the development and progression of both diseases, DPP-IV in glucose uptake and FAS in fatty acid synthesis. In both cases, the molecular mechanisms of how each one acts separately have been described, and which are the key inhibitory drugs and molecules for each one. However, although it is known that there is an association between both clinically and molecularly, the mechanism has not been elucidated; therefore, this review focuses on proposing a mechanism of convergence of DPP-IV and FAS in diabesity, and the possible mode of action in which bioactive peptides obtained from plant and animal sources can inhibit these two enzymes in a similar way as drugs do.
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Affiliation(s)
- Ma. Fabiola León-Galván
- Food Department, Proteomics and Gene Expression Laboratory, University of Guanajuato, Life Science Division, Campus Irapuato-Salamanca, Ex Hacienda el Copal, Carretera Irapuato-Silao km 9.0, Irapuato, C.P 36500 Guanajuato México
- Graduate Program in Biosciences, Proteomics and Gene Expression Laboratory, University of Guanajuato, Life Science Division, Campus Irapuato-Salamanca, Ex Hacienda el Copal, Carretera Irapuato-Silao km 9.0, Irapuato, C.P 36500 Guanajuato México
| | - Daniela Sarahi Medina-Rojas
- Graduate Program in Biosciences, Proteomics and Gene Expression Laboratory, University of Guanajuato, Life Science Division, Campus Irapuato-Salamanca, Ex Hacienda el Copal, Carretera Irapuato-Silao km 9.0, Irapuato, C.P 36500 Guanajuato México
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4
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Howard K, Ferris WF, van de Vyver M. The characterization and comparison of femoral bone-derived skeletal stem cells. Biochimie 2025; 233:88-98. [PMID: 40023362 DOI: 10.1016/j.biochi.2025.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/25/2025] [Accepted: 02/25/2025] [Indexed: 03/04/2025]
Abstract
Skeletal stem cells (SSCs) reside in various niche locations within long bones to maintain bone homeostasis and facilitate fracture repair. Bone fragility, associated with ageing, increases the susceptibility of the femoral head to fractures due to an increase in bone adipocytes and concomitant loss of structural integrity. However, the specific contribution of epiphyseal SSCs to fragility is unknown. To explore this, a comparative analysis was performed on the transcriptional profiles and lineage commitment of Wistar rat femoral SSCs derived from the bone marrow (BM-), diaphyseal cortical bone (CB-) and proximal epiphyseal trabecular bone (PF-SSCs) isolated from the same long bones. SSCs were characterized based on morphology, immunophenotype (CD90/CD45), growth rate (population doubling time), gene expression profiles and differentiation capacity (Oil Red O, Alizarin Red S). qRT-PCR micro-arrays were performed on SSCs to evaluate the expression of stemness, SSC and lineage-specific markers in both undifferentiated and differentiated states. Our findings support the hypothesis that SSCs from different bone regions exhibit distinct transcriptional profiles, reflecting their specific niche environments. CB-SSCs displayed superior osteogenic potential as evidenced by the expression of key osteogenic genes and higher levels of mineralization. In contrast, PF-SSCs had a reduced osteogenic capacity with a higher adipogenic potential. Overall, the study revealed the importance of niche-specific stem cell properties for use in regenerative medicine applications and provides insight into the potential role of PF-SSCs in bone fragility and fracture risk.
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Affiliation(s)
- Kayla Howard
- Experimental Medicine Research Group, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
| | - William Frank Ferris
- Experimental Medicine Research Group, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
| | - Mari van de Vyver
- Experimental Medicine Research Group, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
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Higuchi L, Ouchi N, Negishi Y, Naruo M, Kusano M, Suzuki S, Okuda T, Morita R. Ovariectomy-induced bone loss through inappropriate inflammatory response: an osteoimmunological perspective on postmenopausal osteoporosis. Immunol Med 2025:1-14. [PMID: 40377249 DOI: 10.1080/25785826.2025.2506870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Accepted: 05/12/2025] [Indexed: 05/18/2025] Open
Abstract
Postmenopausal osteoporosis (PO) is a prevalent condition that significantly impairs the quality of life in elderly women. While traditionally attributed to estrogen deficiency, emerging evidence suggests that immune dysregulation plays a critical role in its pathogenesis. This study investigates the osteoimmunological mechanisms underlying PO using an ovariectomy (Ovx) mouse model. Our findings indicate that Ovx mice exhibit substantial reductions in bone mineral density and bone volume, accompanied by a marked suppression of interleukin-4 (IL-4) and interferon-gamma (IFN-γ) production, particularly from natural killer T (NKT) cells. Lipidomic analysis of bone marrow further revealed an upregulation of omega-6 fatty acids, contributing to an inflammatory microenvironment that promotes excessive osteoclast activation. Notably, administration of the glycolipid OCH restored cytokine production and mitigated bone loss in Ovx mice, suggesting its therapeutic potential. These findings highlight the complex interplay between immune responses and lipid metabolism in PO and propose novel therapeutic strategies aimed at modulating immune function to prevent bone loss. This study offers valuable insights into the osteoimmunological mechanisms of PO and underscores the potential of immunomodulatory approaches for its management.
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Affiliation(s)
- Lilika Higuchi
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan
| | - Nozomi Ouchi
- Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan
| | - Yasuyuki Negishi
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan
- Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan
| | - Munehiro Naruo
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan
- Department of Orthopedic Surgery, Tomei Atsugi Hospital, Kanagawa, Japan
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Maiko Kusano
- Department of Legal Medicine, Showa University, Tokyo, Japan
| | - Shunji Suzuki
- Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan
| | - Takahisa Okuda
- Department of Legal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Rimpei Morita
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan
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Ostaszewska A, Michalska Z, Dzierzynska M, Fularczyk M, Bielak K, Morawska A, Kosmala M, Kulig I, Morytz J, Trusiak H, Zimowska M, Rodziewicz-Motowidlo S, Ciemerych MA, Archacka K, Brzoska E. Beneficial but diverse influence of custom-designed hydrogels modified with IL-4 and SDF-1 peptides on selected populations of cells essential for skeletal muscle regeneration. Int J Biol Macromol 2025:144282. [PMID: 40381767 DOI: 10.1016/j.ijbiomac.2025.144282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 04/28/2025] [Accepted: 05/14/2025] [Indexed: 05/20/2025]
Abstract
Under specific circumstances, such as extensive injuries, the development of degenerative diseases, or aging, the naïve potential of skeletal muscle to regenerate may be limited. For this reason, different tools and approaches are being tested which could result in the improvement of skeletal muscle reconstruction. Among them are hydrogels, investigated also by us, additionally functionalized with fragments of proteins known to support skeletal muscle regeneration, i.e., stromal-derived factor 1 or interleukin 4. In the current study, we evaluated the impact of such custom-designed hydrogels on different human cells important for efficient muscle regeneration, i.e., myoblasts, crucial for myofiber reconstruction, fibroblasts, ensuring ECM formation, and endothelial cells, securing new vessel development in regenerated muscles. Our results indicate that hydrogels functionalized with SDF-1 and IL-4 peptides induce beneficial but diverse effects in analyzed cell types, influencing either their proliferation, migration, or differentiation. Most importantly, hydrogels tested by us do not harm analyzed cell types, indicating that in vivo skeletal muscle regeneration might be improved by them.
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Affiliation(s)
- Anna Ostaszewska
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | - Zuzanna Michalska
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | - Maria Dzierzynska
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdańsk, Poland
| | - Martyna Fularczyk
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdańsk, Poland
| | - Kacper Bielak
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | - Agnieszka Morawska
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | - Magdalena Kosmala
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | - Izabela Kulig
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | - Justyna Morytz
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | - Hanna Trusiak
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | - Małgorzata Zimowska
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | | | - Maria A Ciemerych
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdańsk, Poland
| | - Karolina Archacka
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
| | - Edyta Brzoska
- Department of Cytology, Faculty of Biology, Institute of Developmental Biology and Biomedical Sciences, University of Warsaw, Poland
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Santana-Oliveira DA, Souza-Tavares H, Fernandes-da-Silva A, Marinho TS, Silva-Veiga FM, Daleprane JB, Souza-Mello V. Obesity prevention by different exercise protocols (HIIT or MICT) involves beige adipocyte recruitment and improved mitochondrial dynamics in high-fat-fed mice. Mol Cell Endocrinol 2025; 602:112533. [PMID: 40157711 DOI: 10.1016/j.mce.2025.112533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025]
Abstract
AIM This study evaluated the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on UCP1-dependent and UCP1-independent thermogenic and mitochondrial dynamics markers in the inguinal sWAT of high-fat-fed mice. METHODS Sixty male C57BL/6 mice (3 months old) were divided into six experimental groups: control diet (C), C + HIIT (C-HIIT), C + MICT (C-MICT), high-fat diet (HF), HF + HIIT (HF-HIIT) and HF + MICT (HF-MICT). The diet and exercise protocols started simultaneously and lasted ten weeks. RESULTS HIIT and MICT prevented body mass gain and fat pad expansion, improved insulin sensitivity, and induced browning in C-fed and HF-fed animals. Chronic intake of a HF diet caused adipocyte hypertrophy with a proinflammatory adipokine profile and impaired the expression of thermogenic and mitochondrial dynamics markers. However, both exercise intensities increased anti-inflammatory adipokine concentrations and improved gene markers of mitochondrial dynamics, resulting in sustained UCP1-dependent and UCP1-independent thermogenic markers and maintenance of the beige phenotype in inguinal sWAT. The principal component analysis placed all trained groups opposite the HF group and near the C group, ensuring the effectiveness of HIIT and MICT to prevent metabolic alterations. CONCLUSIONS This study provides reliable evidence that, regardless of intensity, exercise is a strategy to prevent obesity by reducing body fat accumulation and inducing browning. The anti-inflammatory adipokine profile and the increased expression of UCP1-dependent and UCP1-independent thermogenic markers sustained active beige adipocytes and mitochondrial enhancement to halt metabolic disturbances due to HF-feeding in exercised mice.
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Affiliation(s)
- Daiana Araujo Santana-Oliveira
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Henrique Souza-Tavares
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Aline Fernandes-da-Silva
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Thatiany Souza Marinho
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Flavia Maria Silva-Veiga
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Julio Beltrame Daleprane
- Laboratory for Studies of Interactions Between Nutrition and Genetics (LEING), Institute of Nutrition, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil.
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Baya NA, Erdem IS, Venkatesh SS, Reibe S, Charles PD, Navarro-Guerrero E, Hill B, Lassen FH, Claussnitzer M, Palmer DS, Lindgren CM. Combining evidence from human genetic and functional screens to identify pathways altering obesity and fat distribution. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2024.09.19.24313913. [PMID: 39371160 PMCID: PMC11451655 DOI: 10.1101/2024.09.19.24313913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Overall adiposity and body fat distribution are heritable traits associated with altered risk of cardiometabolic disease and mortality. Performing rare variant (minor allele frequency<1%) association testing using exome-sequencing data from 402,375 participants in the UK Biobank (UKB) for nine overall and tissue-specific fat distribution traits, we identified 19 genes where putatively damaging rare variation associated with at least one trait (Bonferroni-adjusted P <1.58×10 -7 ) and 50 additional genes at FDR≤1% ( P ≤4.37×10 -5 ). These 69 genes exhibited significantly higher (one-sided t -test P =3.58×10 -18 ) common variant prioritisation scores than genes not significantly enriched for rare putatively damaging variation, with evidence of monotonic allelic series (dose-response relationships) among ultra-rare variants (minor allele count≤10) in 22 genes. Combining rare and common variation evidence, allelic series and longitudinal analysis, we selected 14 genes for CRISPR knockdown in human white adipose tissue cell lines. In three previously uncharacterised target genes, knockdown increased (two-sided t -test P <0.05) lipid accumulation, a cellular phenotype relevant for fat mass traits, compared to Cas9-empty negative controls: COL5A3 (fold change [FC]=1.72, P =0.0028), EXOC7 (FC=1.35, P =0.0096), and TRIP10 (FC=1.39, P =0.0157); furthermore, knockdown of PPARG (FC=0.25, P =5.52×10 -7 ) and SLTM (FC=0.51, P =1.91×10 -4 ) resulted in reduced lipid accumulation. Integrating across population-based genetic and in vitro functional evidence, we highlight therapeutic avenues for altering obesity and body fat distribution by modulating lipid accumulation.
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Chang MM, Chu DT, Lin SC, Lee JS, Vu TD, Vu HT, Ramasamy TS, Lin SP, Wu CC. Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy. Stem Cell Res Ther 2025; 16:129. [PMID: 40069892 PMCID: PMC11899936 DOI: 10.1186/s13287-025-04164-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 01/21/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Microenvironmental alterations induce significant genetic and epigenetic changes in stem cells. Mitochondria, essential for regenerative capabilities, provide the necessary energy for stem cell function. However, the specific roles of histone modifications and mitochondrial dynamics in human adipose-derived stem cells (ASCs) during morphological transformations remain poorly understood. In this study, we aim to elucidate the mechanisms by which ASC sphere formation enhances mitochondrial function, delivery, and rescue efficiency. METHODS ASCs were cultured on chitosan nano-deposited surfaces to form 3D spheres. Mitochondrial activity and ATP production were assessed using MitoTracker staining, Seahorse XF analysis, and ATP luminescence assays. Single-cell RNA sequencing, followed by Ingenuity Pathway Analysis (IPA), was conducted to uncover key regulatory pathways, which were validated through molecular techniques. Pathway involvement was confirmed using epigenetic inhibitors or PPARγ-modulating drugs. Mitochondrial structural integrity and delivery efficiency were evaluated after isolation. RESULTS Chitosan-induced ASC spheres exhibited unique compact mitochondrial morphology, characterized by condensed cristae, enhanced mitochondrial activity, and increased ATP production through oxidative phosphorylation. High expressions of mitochondrial complex I genes and elevated levels of mitochondrial complex proteins were observed without an increase in reactive oxygen species (ROS). Epigenetic modification of H3K27me3 and PPARγ involvement were discovered and confirmed by inhibiting H3K27me3 with the specific EZH2 inhibitor GSK126 and by adding the PPARγ agonist Rosiglitazone (RSG). Isolated mitochondria from ASC spheres showed improved structural stability and delivery efficiency, suppressed the of inflammatory cytokines in LPS- and TNFα-induced inflamed cells, and rescued cells from damage, thereby enhancing function and promoting recovery. CONCLUSION Enhancing mitochondrial ATP production via the EZH2-H3K27me3-PPARγ pathway offers an alternative strategy to conventional cell-based therapies. High-functional mitochondria and delivery efficiency show significant potential for regenerative medicine applications.
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Affiliation(s)
- Ming-Min Chang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan
- Medical Device Innovation Center, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Dinh Toi Chu
- Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, 1000, Vietnam
| | - Sheng-Che Lin
- Division of Plastic and Reconstructive Surgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, 70965, Taiwan
| | - Jung-Shun Lee
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan
- Division of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, 701401, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Thuy Duong Vu
- Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, 1000, Vietnam
| | - Hue Thi Vu
- Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, 1000, Vietnam
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Shau-Ping Lin
- Institute of Biotechnology, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, 10672, Taiwan
| | - Chia-Ching Wu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan.
- Medical Device Innovation Center, National Cheng Kung University, Tainan, 70101, Taiwan.
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, 70101, Taiwan.
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, 70101, Taiwan.
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10
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Kim A, Jung S, Kim Y, Jung J, Lee S, Lee H, Kim MJ, Park JY, Hwang EM, Lee J. Novel function of TREK-1 in regulating adipocyte differentiation and lipid accumulation. Cell Death Dis 2025; 16:164. [PMID: 40057491 PMCID: PMC11890776 DOI: 10.1038/s41419-025-07478-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 02/07/2025] [Accepted: 02/24/2025] [Indexed: 05/13/2025]
Abstract
K2P (two-pore domain potassium) channels, a diversified class of K+-selective ion channels, have been found to affect a wide range of physiological processes in the body. Despite their established significance in regulating proliferation and differentiation in multiple cell types, K2P channels' specific role in adipogenic differentiation (adipogenesis) remains poorly understood. In this study, we investigated the engagement of K2P channels, specifically KCNK2 (also known as TREK-1), in adipogenesis using primary cultured adipocytes and TREK-1 knockout (KO) mice. Our findings showed that TREK-1 expression in adipocytes decreases substantially during adipogenesis. This typically causes an increased Ca2+ influx and alters the electrical potential of the cell membrane in 3T3-L1 cell lines. Furthermore, we observed an increase in differentiation and lipid accumulation in both 3T3-L1 cell lines and primary cultured adipocytes when the TREK-1 activity was blocked with Spadin, the specific inhibitors, and TREK-1 shRNA. Finally, our findings revealed that mice lacking TREK-1 gained more fat mass and had worse glucose tolerance when fed a high-fat diet (HFD) compared to the wild-type controls. The findings demonstrate that increase of the membrane potential at adipocytes through the downregulation of TREK-1 can influence the progression of adipogenesis.
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Affiliation(s)
- Ajung Kim
- Food Functionality Research Division, Korea Food Research Institute, Wanju, 55365, South Korea
- Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, South Korea
| | - Seoyeong Jung
- Food Functionality Research Division, Korea Food Research Institute, Wanju, 55365, South Korea
- School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, 02841, South Korea
| | - Yongeun Kim
- Food Functionality Research Division, Korea Food Research Institute, Wanju, 55365, South Korea
| | - Jonghoon Jung
- Food Functionality Research Division, Korea Food Research Institute, Wanju, 55365, South Korea
| | - Soomin Lee
- Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, South Korea
- School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, 02841, South Korea
| | - Hojin Lee
- Food Functionality Research Division, Korea Food Research Institute, Wanju, 55365, South Korea
- School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, 02841, South Korea
| | - Min Jung Kim
- Food Functionality Research Division, Korea Food Research Institute, Wanju, 55365, South Korea
| | - Jae-Yong Park
- School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, 02841, South Korea
| | - Eun Mi Hwang
- Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, South Korea.
| | - Jaekwang Lee
- Food Functionality Research Division, Korea Food Research Institute, Wanju, 55365, South Korea.
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11
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Tao T, Xu Y, Zhang CH, Zhang X, Chen J, Liu J. Single-cell transcriptomic analysis and luteolin treatment reveal three adipogenic genes, including Aspn, Htra1 and Efemp1. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159585. [PMID: 39662603 DOI: 10.1016/j.bbalip.2024.159585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 12/01/2024] [Accepted: 12/07/2024] [Indexed: 12/13/2024]
Abstract
A comparative transcriptomic analysis in adipose stem and progenitor cells (ASPCs) between obese and lean mice might facilitate the identification of novel adipogenic genes. Here, we compare transcriptomic differences in the ASPCs of subcutaneous adipose tissue (SAT) between the mice fed on a high-fat-diet (HFD) and the chow diet (CD)-fed mice by analyzing three independent single-cell RNA sequencing datasets. Six differential genes, including three up-regulated genes Aspn, Rrbp1, Fbln2 and three down-regulated genes Htra1, Plpp3, Efemp1, are identified and confirmed in HFD-fed mice. Further, the expression of these genes is found to be significantly diminished in the differentiated 3T3-L1 cells. Treatment with luteolin, a dietary flavonoid known to inhibit 3T3-L1 adipogenesis, reverses the decreased expression of Aspn, Htra1 and Efemp1. Furthermore, knockdown of Aspn, Htra1 and Efemp1 significantly facilitates 3T3-L1 adipogenesis. Together, these genes not only are differential in ASPCs between obese and lean mice, but also are the adipogenic inhibitory genes that can be up-regulated by luteolin treatment.
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Affiliation(s)
- Tao Tao
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Yanting Xu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Cheng-Hui Zhang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Xian Zhang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, China.
| | - Juan Chen
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, China.
| | - Jian Liu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, China.
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12
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Castro É, Vieira TS, Peixoto ÁS, Leonardi BF, Tomazelli CA, Lino CA, Oliveira TE, Pessoa NM, Pessoa EVM, Abe-Honda MA, Pontara-Corte N, Silva-Junior LP, Pires AB, Chaves-Filho AB, Moustaid-Moussa N, Festuccia WT. Fish Oil and EPA Improve Insulin Sensitivity, in Part Through Adipocyte mTORC2 Activation in Diet-Induced Obese Male Mice. Mol Nutr Food Res 2025; 69:e70001. [PMID: 39961050 DOI: 10.1002/mnfr.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 12/24/2024] [Accepted: 01/23/2025] [Indexed: 03/21/2025]
Abstract
Fish oil rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) improves rodent glucose homeostasis and insulin sensitivity through unknown mechanisms. We investigated the involvement of adipocyte Rictor/mTORC2 as a mediator of fish oil and n-3 PUFA eicosapentaenoic acid (EPA) effects. Male mice bearing or not Rictor/mTORC2 deficiency in adipocytes were fed isocaloric high fat diets produced either with lard (HFD) or fish oil (HFn3) and evaluated for glucose homeostasis and insulin sensitivity. HFn3 intake improved glucose tolerance and insulin sensitivity, increased glucose uptake in adipose tissue and skeletal muscle per unit of insulin, and reduced hepatic glucose production as well as adipose tissue and liver de novo fatty acid synthesis. Interestingly, this improvement in glucose homeostasis was concurrent with low serum insulin levels and increased content of Ser473 phosphorylated (p) Akt in adipose tissue, but not skeletal muscle and liver. Intake of an HFD supplemented with EPA increased, in an mTORC2-dependent manner, insulin sensitivity and adipocyte pAkt Ser473, but not glucose tolerance. In conclusion, adipocyte mTORC2 mediates in part the improvement in insulin sensitivity induced by fish oil and EPA, while the improvement in glucose tolerance induced by fish oil seems to be triggered by mTORC2-independent actions in muscle and liver.
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Affiliation(s)
- Érique Castro
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Thayna S Vieira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Álbert S Peixoto
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Bianca F Leonardi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Caroline A Tomazelli
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Caroline A Lino
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Tiago E Oliveira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Natália M Pessoa
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Erika V M Pessoa
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Marina A Abe-Honda
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Natália Pontara-Corte
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Luciano P Silva-Junior
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Ana B Pires
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Adriano B Chaves-Filho
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, Texas Tech University, Lubbock, Texas, USA
- Obesity Research Institute, Texas Tech University, Lubbock, Texas, USA
| | - William T Festuccia
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
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13
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Ma H, Lu Y, Chen W, Gao Z, Wu D, Chong Y, Wu J, Xi D, Deng W, Hong J. Multiple omics analysis reveals the regulation of SIRT4 on lipid deposition and metabolism during the differentiation of bovine preadipocytes. Genomics 2025; 117:111006. [PMID: 39875030 DOI: 10.1016/j.ygeno.2025.111006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 01/18/2025] [Accepted: 01/20/2025] [Indexed: 01/30/2025]
Abstract
The differentiation and lipid metabolism of preadipocytes are crucial processes in IMF deposition. Studies have demonstrated that SIRT4 plays essential roles in energy metabolism and redox homeostasis, with its expression being coordinately regulated by multiple transcription factors associated with energy and lipid metabolism. In this study, the findings of multiple omics analysis reveal that SIRT4 significantly up-regulates the expression of genes involved in adipogenesis and enhances the differentiation and lipid deposition of bovine preadipocytes. Furthermore, SIRT4 profoundly influences the expression pattern of metabolites by increasing the abundance of substances involved in lipid synthesis while decreasing those that promote lipid oxidative decomposition. Additionally, SIRT4 broadly up-regulates the expression levels of various lipid classes, including glycerolipids, glycerophospholipids, sphingolipids, and sterol lipids. These findings not only provide a theoretical basis for molecular breeding and genetic improvement in beef cattle, but also offer potential therapeutic approaches for energy homeostasis disorders and obesity.
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Affiliation(s)
- Hongming Ma
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Ying Lu
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Wei Chen
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Zhendong Gao
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Dongwang Wu
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Yuqing Chong
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Jiao Wu
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Dongmei Xi
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Weidong Deng
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Jieyun Hong
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China.
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14
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Lim B, Kamal A, Gomez Ramos B, Adrian Segarra JM, Ibarra IL, Dignas L, Kindinger T, Volz K, Rahbari M, Rahbari N, Poisel E, Kafetzopoulou K, Böse L, Breinig M, Heide D, Gallage S, Barragan Avila JE, Wiethoff H, Berest I, Schnabellehner S, Schneider M, Becker J, Helm D, Grimm D, Mäkinen T, Tschaharganeh DF, Heikenwalder M, Zaugg JB, Mall M. Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis. Nat Genet 2025; 57:668-679. [PMID: 39948437 PMCID: PMC11906372 DOI: 10.1038/s41588-025-02081-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 01/08/2025] [Indexed: 02/20/2025]
Abstract
Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.
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Affiliation(s)
- Bryce Lim
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Aryan Kamal
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Borja Gomez Ramos
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Juan M Adrian Segarra
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ignacio L Ibarra
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany
| | - Lennart Dignas
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Tim Kindinger
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kai Volz
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Mohammad Rahbari
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nuh Rahbari
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of General and Visceral Surgery, University of Ulm, Ulm, Germany
| | - Eric Poisel
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kanela Kafetzopoulou
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lio Böse
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Marco Breinig
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Danijela Heide
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
| | - Suchira Gallage
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
- Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Faculty of Medicine, University Tuebingen, Tübingen, Germany
| | | | - Hendrik Wiethoff
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Ivan Berest
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany
| | - Sarah Schnabellehner
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | | | - Jonas Becker
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty and Faculty of Engineering Sciences, Heidelberg University, Center for Integrative Infectious Diseases Research (CIID), BioQuant, Heidelberg, Germany
| | - Dominic Helm
- Proteomics Core Facility, DKFZ, Heidelberg, Germany
| | - Dirk Grimm
- Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty and Faculty of Engineering Sciences, Heidelberg University, Center for Integrative Infectious Diseases Research (CIID), BioQuant, Heidelberg, Germany
- German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg, Heidelberg, Germany
| | - Taija Mäkinen
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Translational Cancer Medicine Program and Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
| | - Darjus F Tschaharganeh
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
- Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Faculty of Medicine, University Tuebingen, Tübingen, Germany
| | - Judith B Zaugg
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany.
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
| | - Moritz Mall
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany.
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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15
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Silva AVL, Lima RP, Oliveira FTB, Quinderé ALG, Benevides NMB, Santos FA. Sulfated galactan from Acanthophora muscoides inhibits adipogenesis via regulating adipogenic transcription factors and AMPK in 3T3-L1 cells. BRAZ J BIOL 2025; 85:e289036. [PMID: 39969001 DOI: 10.1590/1519-6984.289036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 12/07/2024] [Indexed: 02/20/2025] Open
Abstract
Obesity is a global public health issue, closely linked to cardiovascular disease and type 2 diabetes. Pharmacological interventions for weight loss are one option for treating obesity; however, these drugs often come with side effects or limited efficacy, highlighting the need for new therapies. Marine algae offer a promising source of biologically active compounds for human health, including antidiabetic, anti-inflammatory, and anti-obesity properties. Sulfated galactan isolated from the red marine algae Acanthophora muscoides (SGAM) has demonstrated diverse biological activities including anti-inflammatory activity in vivo and in vitro studies. However, its potential impact on adipogenesis remains unexplored. This study evaluated the effect of SGAM on adipogenesis in 3T3-L1 cells using Oil Red O staining and analyzed the protein expression of key transcription factors associated with adipogenesis. SGAM (25-100 μg/mL) was found to reduce intracellular lipid accumulation in adipocytes without compromising cell viability. Furthermore, our findings suggest that SGAM significantly inhibits adipocyte differentiation by downregulating the expression of key adipogenesis-related transcription factors, including C/EBPβ, C/EBPδ, C/EBPα, and PPARγ. Additionally, SGAM reduced the protein expression of SREBP-1 and promoted the activation of AMPK. In conclusion, SGAM inhibits adipogenesis by negatively modulating the expression of the main adipogenic transcription factors and activating AMPK.
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Affiliation(s)
- A V L Silva
- Universidade Federal do Ceará - UFC, Faculdade de Medicina, Departamento de Fisiologia e Farmacologia, Laboratório de Produtos Naturais, Fortaleza, CE, Brasil
| | - R P Lima
- Universidade Federal do Ceará - UFC, Faculdade de Medicina, Departamento de Fisiologia e Farmacologia, Laboratório de Produtos Naturais, Fortaleza, CE, Brasil
| | - F T B Oliveira
- Universidade Federal do Ceará - UFC, Faculdade de Medicina, Departamento de Fisiologia e Farmacologia, Laboratório de Produtos Naturais, Fortaleza, CE, Brasil
| | - A L G Quinderé
- Universidade Federal do Ceará - UFC, Faculdade de Medicina, Departamento de Fisiologia e Farmacologia, Laboratório de Produtos Naturais, Fortaleza, CE, Brasil
| | - N M B Benevides
- Universidade Federal do Ceará - UFC, Departamento de Bioquímica e Biologia Molecular, Laboratório de Carboidratos e Lectinas, Fortaleza, CE, Brasil
| | - F A Santos
- Universidade Federal do Ceará - UFC, Faculdade de Medicina, Departamento de Fisiologia e Farmacologia, Laboratório de Produtos Naturais, Fortaleza, CE, Brasil
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16
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Jiang L, Sun X, Wan Y, Qin Q, Xu M, Ma J, Zan L, Wang H. Transcriptome Reveals the Promoting Effect of Beta-Sitosterol on the Differentiation of Bovine Preadipocytes. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:3400-3412. [PMID: 39874185 DOI: 10.1021/acs.jafc.4c10452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
Natural small molecule compounds play crucial roles in regulating fat deposition. Beta-sitosterol exhibits multiple biological activities such as cholesterol reduction and anticancer effects. However, its regulatory mechanism in the differentiation of bovine preadipocytes remains unclear. We identified potential associations of Beta-sitosterol with biological processes such as cholesterol regulation and lipid metabolism through the prediction of its targets. We utilized techniques such as Oil Red O staining, Western blotting, RNA-seq, and others to elucidate the promoting effect of Beta-sitosterol on the differentiation of bovine preadipocytes. Furthermore, reducing the expression of the most downregulated gene among differential expressed genes (DEGs), MGP, promotes the differentiation of bovine preadipocytes. After interfering with MGP, RNA-seq analysis on the sixth day of differentiation revealed that DEGs were most significantly enriched in the PPAR signaling pathway. In this pathway, the expression levels of genes related to adipocyte differentiation, including CD36, RXRα, RXRγ, FABP4, PLIN1, ADIPO, and CAP, were significantly upregulated (P < 0.01). Western blot and ELISA analysis on genes related to the PPAR signaling pathway showed that interfering with MGP increased the expression of proteins such as RXRα, indicating the possible activation of the PPAR signaling pathway. In summary, Beta-sitosterol may promote the differentiation of bovine preadipocytes by reducing the expression of MGP, thereby activating the PPAR signaling pathway.
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Affiliation(s)
- Lei Jiang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xiaolei Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yuan Wan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Qihua Qin
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Min Xu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jianqiang Ma
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Linsen Zan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
- National Beef Cattle Improvement Centre, Yangling, Shaanxi 712100, China
| | - Hongbao Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
- National Beef Cattle Improvement Centre, Yangling, Shaanxi 712100, China
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17
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Senthil Kumar J, Mehboob MZ, Lei X. Exploring CTRP6: a biomarker and therapeutic target in metabolic diseases. Am J Physiol Endocrinol Metab 2025; 328:E139-E147. [PMID: 39701154 DOI: 10.1152/ajpendo.00353.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/11/2024] [Accepted: 12/11/2024] [Indexed: 12/21/2024]
Abstract
The rising prevalence of metabolic diseases is a significant global health concern. Beyond lifestyle management, targeting key molecules involved in metabolic regulation is essential. C1q/TNF-related protein 6 (CTRP6) is notably associated with glucose and lipid metabolism, with numerous studies highlighting its regulatory functions in metabolic diseases. This review summarizes the current knowledge on CTRP6, focusing on its gene expression profiles, protein structure, gene regulation, and role in metabolic diseases. CTRP6 is widely expressed across various tissues and features four distinct domains, with the C1q domain predicted to bind to its receptor. Notably, serum levels of CTRP6 are significantly elevated in patients with obesity and type 2 diabetes. In these conditions, adipose tissue serves as a key source of CTRP6 and its involvement in adipose tissue expansion, inflammation, and nutrient sensing has been observed in several studies. CTRP6 is also implicated in type 1 diabetes, gestational diabetes mellitus, and diabetic complications, particularly diabetic nephropathy. Although some studies have suggested that CTRP6 has protective roles in atherosclerotic cell models, myocardial infarction rat models, and ischemia/reperfusion injury mouse models, methodological issues such as unreliable antibodies and unstrict controls make it difficult to draw accurate conclusions from these studies. Patients with polycystic ovary syndrome (PCOS) exhibit elevated serum levels of CTRP6, although its direct impact on PCOS phenotypes remains unclear. In conclusion, CTRP6 emerges as a promising therapeutic target for metabolic diseases. A deeper understanding of CTRP6 will empower the scientific community to develop effective interventions to address the increasing prevalence of these diseases.
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Affiliation(s)
- Jeevotham Senthil Kumar
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, United States
| | - Muhammad Zubair Mehboob
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, United States
| | - Xia Lei
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, United States
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18
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Zeng S, Li Z, Li X, Du Q, Zhang Y, Zhong Z, Wang H, Zhang S, Li P, Li H, Chen L, Jiang A, Shang P, Li M, Long K. Inhibition of triglyceride metabolism-associated enhancers alters lipid deposition during adipocyte differentiation. FASEB J 2025; 39:e70347. [PMID: 39873971 PMCID: PMC11774232 DOI: 10.1096/fj.202401137r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 12/28/2024] [Accepted: 01/09/2025] [Indexed: 01/30/2025]
Abstract
Triglyceride (TG) metabolism is a complex and highly coordinated biological process regulated by a series of genes, and its dysregulation can lead to the occurrence of disorders in lipid metabolism. However, the transcriptional regulatory mechanisms of crucial genes in TG metabolism mediated by enhancer-promoter interactions remain elusive. Here, we identified candidate enhancers regulating the Agpat2, Dgat1, Dgat2, Pnpla2, and Lipe genes in 3T3-L1 adipocytes by integrating epigenomic data (H3K27ac, H3K4me1, and DHS-seq) with chromatin three-dimensional interaction data. Luciferase reporter assays revealed that 11 enhancers exhibited fluorescence activity. The repression of enhancers using the dCas9-KRAB system revealed the functional roles of enhancers of Dgat2 and Pnpla2 in regulating their expression and TG metabolism. Furthermore, transcriptome analyses revealed that inhibition of Dgat2-En4 downregulated pathways associated with lipid metabolism, lipid biosynthesis, and adipocyte differentiation. Additionally, overexpression and motif mutation experiments of transcription factor found that two TFs, PPARG and RXRA, regulate the activity of Agpat2-En1, Dgat2-En4, and Pnpla2-En5. Our study identified functional enhancers regulating TG metabolism and elucidated potential regulatory mechanisms of TG deposition from enhancer-promoter interactions, providing insights into understanding lipid deposition.
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Affiliation(s)
- Sha Zeng
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Ziqi Li
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Xiaokai Li
- Chongqing Academy of Animal SciencesChongqingChina
- National Center of Technology Innovation for PigsChongqingChina
| | - Qinjiao Du
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Yu Zhang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Zhining Zhong
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Haoming Wang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Songling Zhang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Penghao Li
- Jinxin Research Institute for Reproductive Medicine and GeneticsSichuan Jinxin Xi'nan Women's and Children's HospitalChengduChina
| | - Haohuan Li
- College of Veterinary MedicineSichuan Agricultural UniversityChengduChina
| | - Li Chen
- Chongqing Academy of Animal SciencesChongqingChina
- National Center of Technology Innovation for PigsChongqingChina
| | - Anan Jiang
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Peng Shang
- Animal Science CollegeTibet Agriculture and Animal Husbandry UniversityLinzhiChina
| | - Mingzhou Li
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
| | - Keren Long
- State Key Laboratory of Swine and Poultry Breeding IndustrySichuan Agricultural UniversityChengduChina
- College of Animal Science and TechnologySichuan Agricultural UniversityChengduChina
- Chongqing Academy of Animal SciencesChongqingChina
- National Center of Technology Innovation for PigsChongqingChina
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19
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Pimenta EM, Garza AE, Camp SY, Park J, Hoffman SE, Valderrábano L, Fu J, Bi K, Karam J, Titchen BM, Khandekar MJ, Shannon E, Kang YJ, Nag A, Thorner AR, Raut CP, Hornick JL, Merriam P, Solimini NL, George S, Demetri GD, Van Allen EM. Epigenetic dysregulation of metabolic programs mediates liposarcoma cell plasticity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.20.633920. [PMID: 39896505 PMCID: PMC11785083 DOI: 10.1101/2025.01.20.633920] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Sarcomas are rare connective tissue cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) holds valuable insights into dysfunctional differentiation given its well- and dedifferentiated histologic subtypes (WDLPS, DDLPS). Despite well-established differences in histology and clinical behavior, the molecular pathways underlying each subtype are poorly understood. Here, we performed single-nucleus multiome sequencing and spatial profiling on carefully curated human LPS samples and found defects in adipocyte-specific differentiation within LPS. Loss of insulin-like growth factor 1 (IGF1) and gain of cellular programs related to early mesenchymal development and glucagon-like peptide-1 (GLP-1)-induced insulin secretion are primary features of DDLPS. IGF1 loss was associated with worse overall survival in LPS patients. Through in vitro stimulation of the IGF1 pathway, we identified that DDLPS cells are deficient in the adipose-specific PPARG isoform 2 (PPARG2). Defects in IGF1/PPARG2 signaling in DDLPS led to a block in differentiation that could not be fully overcome with the addition of exogenous IGF1 or the pro-adipogenic agonists to PPARG and GLP-1. However, we noted upregulation of the IGF1 receptor (IGF1R) in the setting of IGF1 deficiency, which promoted sensitivity to an IGF1R-targeted antibody-drug conjugate that may serve as a novel therapeutic strategy in LPS. In summary, lineage-specific defects in adipogenesis drive dedifferentiation in LPS and may translate into selective therapeutic targeting in this disease.
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Affiliation(s)
- Erica M. Pimenta
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Sarcoma Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- David Liposarcoma Research Initiative, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Amanda E. Garza
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Sabrina Y. Camp
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Jihye Park
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Samantha E. Hoffman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Division of Medical Sciences PhD Program in Biological and Biomedical Sciences, Boston, MA 02115, USA
- Harvard-MIT MD-PhD Program, Harvard Medical School, Boston, MA, 02115, USA
| | - Laura Valderrábano
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Jingxin Fu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, 02115, USA
| | - Kevin Bi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
| | - Julie Karam
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Breanna M. Titchen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Harvard Division of Medical Sciences PhD Program in Biological and Biomedical Sciences, Boston, MA 02115, USA
| | - Melin J. Khandekar
- David Liposarcoma Research Initiative, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Erin Shannon
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Yun Jee Kang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA, 02115, USA
| | - Anwesha Nag
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
| | - Aaron R. Thorner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
| | - Chandrajit P. Raut
- Sarcoma Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA, 02115, USA
| | - Jason L. Hornick
- Sarcoma Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, 02115, USA
| | - Priscilla Merriam
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Sarcoma Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Nicole L. Solimini
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Sarcoma Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- David Liposarcoma Research Initiative, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Ludwig Center at Harvard, Boston, MA, 02115, USA
| | - Suzanne George
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Sarcoma Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - George D. Demetri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Sarcoma Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- David Liposarcoma Research Initiative, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Ludwig Center at Harvard, Boston, MA, 02115, USA
| | - Eliezer M. Van Allen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- David Liposarcoma Research Initiative, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Parker Institute for Cancer Immunotherapy, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
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20
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Shao Y, Du Y, Chen Z, Xiang L, Tu S, Feng Y, Hou Y, Kou X, Ai H. Mesenchymal stem cell-mediated adipogenic transformation: a key driver of oral squamous cell carcinoma progression. Stem Cell Res Ther 2025; 16:12. [PMID: 39849541 PMCID: PMC11755832 DOI: 10.1186/s13287-025-04132-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 01/08/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Interaction between mesenchymal stem cells (MSCs) and oral squamous cell carcinoma (OSCC) cells plays a major role in OSCC progression. However, little is known about adipogenic differentiation alteration in OSCC-derived MSCs (OSCC-MSCs) and how these alterations affect OSCC growth. METHODS MSCs were successfully isolated and cultured from normal gingival tissue, OSCC peritumoral tissue, and OSCC tissue. This included gingiva-derived MSCs (GMSCs), OSCC adjacent noncancerous tissues-derived MSCs (OSCCN-MSCs), and OSCC-MSCs. The adipogenic and osteogenic differentiation capabilities of these cells were evaluated using Oil Red O and Alizarin Red S staining, respectively. OSCC cells were then co-cultured with either OSCC-MSCs or GMSCs to assess the impact on OSCC cell proliferation and migration. Subcutaneous xenograft experiments were conducted in BALB/c-nu mice to further investigate the effects in vivo. Additionally, immunohistochemical staining was performed on clinical samples to determine the expression levels of fatty acid synthase (FASN) and the proliferation marker Ki67. RESULTS OSCC-MSCs exhibited enhanced adipogenic differentiation and reduced osteogenic differentiation compared to GMSCs. OSCC-MSCs significantly increased the proliferation and migration of OSCC cells relative to GMSCs and promoted tumor growth in mouse xenografts. Lipid droplet accumulation in the stroma was significantly more pronounced in OSCC + OSCC-MSCs xenografts compared to OSCC + GMSCs xenografts. Free fatty acids (FFAs) levels were elevated in OSCC tissues compared to normal gingival tissues. Moreover, OSCC-MSCs consistently secreted higher levels of FFAs in condition medium than GMSCs. Knockdown of FASN in OSCC-MSCs reduced their adipogenic potential and inhibited their ability to promote OSCC cell proliferation and migration. Clinical sample analysis confirmed higher FASN expression in OSCC stroma, correlating with larger tumor size and increased Ki67 expression in cancer tissues, and was associated with poorer overall survival. CONCLUSIONS OSCC-MSCs promoted OSCC proliferation and migration by upregulating FASN expression and facilitating FFAs secretion. Our results provide new insight into the mechanism of OSCC progression and suggest that the FASN of OSCC-MSCs may be potential targets of OSCC in the future.
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Affiliation(s)
- Yiting Shao
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yu Du
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Zheng Chen
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Lei Xiang
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Shaoqin Tu
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yi Feng
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yuluan Hou
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Xiaoxing Kou
- Hospital of Stomatology, Guanghua School of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China.
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
| | - Hong Ai
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
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21
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Shahbazi AS, Irandoost F, Mahdavian R, Shojaeilangari S, Allahvardi A, Naderi-Manesh H. A multi-stage weakly supervised design for spheroid segmentation to explore mesenchymal stem cell differentiation dynamics. BMC Bioinformatics 2025; 26:20. [PMID: 39825265 PMCID: PMC11742216 DOI: 10.1186/s12859-024-06031-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 12/27/2024] [Indexed: 01/20/2025] Open
Abstract
There is a growing interest in utilizing 3D culture models for stem cell and cancer cell research due to their closer resemblance to in vivo environments. In this study, human mesenchymal stem cells (MSCs) were cultured using adipocytes and osteocytes as differentiative mediums on varying concentrations of chitosan substrate. Light microscopy was employed to capture cell images from the first day to the 21st day of differentiation. Accurate image segmentation is crucial for analyzing the morphological features of the spheroids during the experimental period and for understanding MSC differentiation dynamics for therapeutic applications. Therefore, we developed an innovative, weakly supervised model, aided by convolutional neural networks, to perform label-free spheroid segmentation. Since obtaining pixel-level ground truth labels through manual annotation is labor-intensive, our approach improves the overall quality of the ground-truth map by incorporating a multi-stage process within a weakly supervised learning framework. Additionally, we developed a robust learning scheme for spheroid detection, providing a reliable foundation to study MSC differentiation dynamics. The proposed framework was systematically evaluated using low-resolution microscopic data and challenging, noisy backgrounds. The experimental results demonstrate the effectiveness of our segmentation approach in accurately separating the spheroid from the background. Furthermore, it achieves performance comparable to fully supervised state-of-the-art approaches. To quantitatively evaluate our algorithm, extensive experiments were conducted using available annotated data, confirming the reliability and robustness of our method. Our computationally extracted features can confirm the experimental results regarding alterations in MSC viability, attachment, and differentiation dynamics among the substrates with three concentrations of chitosan used. We observed the formation of more compact spheroids with higher solidity and convex area, resulting improved cell attachment and viability on the 2% chitosan substrate. Additionally, this substrate exhibited a higher propensity for differentiation into osteocytes, as evidenced by the formation of smaller and more ellipsoid spheroids. "Chitosan biofilms mimic in vivo environments for stem cell culture, advancing therapeutic and fundamental applications.” "Innovative weakly supervised model enables label-free spheroid segmentation in stem cell differentiation studies.” "Robust learning scheme achieves accurate spheroid separation, comparable to state-of-the-art approaches.”
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Affiliation(s)
- Arash Shahbazpoor Shahbazi
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, 14115-111, Iran
| | - Farzin Irandoost
- Department of Physics, Shahid Beheshti University (SBU Physics), Tehran, Iran
| | - Reza Mahdavian
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, 14115-111, Iran
| | - Seyedehsamaneh Shojaeilangari
- Biomedical Engineering Group, Department of Electrical and Information Technology, Iranian Research Organization for Science and Technology (IROST), Tehran, 33535111, Iran.
| | - Abdollah Allahvardi
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, 14115-111, Iran
| | - Hossein Naderi-Manesh
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, 14115-111, Iran.
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22
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Du Y, Huo Y, Yang Y, Lin P, Liu W, Wang Z, Zeng W, Li J, Liang Z, Yuan C, Zhu J, Luo Z, Liu Y, Ma C, Yang C. Role of sirtuins in obesity and osteoporosis: molecular mechanisms and therapeutic targets. Cell Commun Signal 2025; 23:20. [PMID: 39799353 PMCID: PMC11724515 DOI: 10.1186/s12964-024-02025-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/30/2024] [Indexed: 01/15/2025] Open
Abstract
The prevalence of obesity and osteoporosis (OP) represents a significant public health concern on a global scale. A substantial body of evidence indicates that there is a complex relationship between obesity and OP, with a correlation between the occurrence of OP and obesity. In recent years, sirtuins have emerged as a prominent area of interest in the fields of aging and endocrine metabolism. Among the various research avenues exploring the potential of sirtuins, the effects of these proteins on obesity and OP have garnered significant attention from numerous researchers. Sirtuins regulate energy balance and lipid balance, which in turn inhibit the process of adipogenesis. Additionally, sirtuins regulate the balance between osteogenic and osteoblastic activity, which protects against the development of OP. However, no study has yet provided a comprehensive discussion of the relationship between the three: sirtuins, obesity, and OP. This paper will therefore describe the relationship between sirtuins and obesity, the relationship between sirtuins and OP, and a discussion focusing on the possibility of treating OP caused by obesity by targeting sirtuins. This will be based on the common influences on the occurrence of obesity and OP (such as mesenchymal stem cells, gut microbiota, and insulin). Finally, the potential of SIRT1, an important member of sirtuins, in polyphenolic natural products for the treatment of obesity and OP will be presented. This will contribute to a better understanding of the interactions between sirtuins and obesity and bone, which will facilitate the development of new therapeutic strategies for obesity and OP in the future.
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Grants
- Nos. 2021B1515140012, 2023A1515010083 the Natural Science Foundation of Guangdong Province
- No. 20211800905342 the Dongguan Science and Technology of Social Development Program
- No. A2024398 the Medical Scientific Research Foundation of Guangdong Province
- No. k202005 the Research and Development Fund of Dongguan People' s Hospital
- Nos. GDMU2021003, GDMU2021049, GDMU2022031, GDMU2022047, GDMU2022063, GDMU2022077, GDMU2022078, GDMU2023008, GDMU2023015, GDMU2023026, GDMU2023042, GDMU2023102 the Guangdong Medical University Students' Innovation and Entrepreneurship Training Program
- Nos. 202210571008, S202210571075, 202310571031, S202310571047, S202310571078, S202310571063, S202310571077 the Provincial and National College Students' Innovation and Entrepreneurship Training Program
- No. 4SG24028G the Guangdong Medical University-Southern Medical University twinning research team project
- No. PF100-2-01 "Climbing 100" Joint Merit Training Program Funded Project
- Nos. 2023ZYDS001, 2023FZDS001, 2023FYDB010 the Guangdong Medical University Students' Innovation Experiment Program
- the Research and Development Fund of Dongguan People’ s Hospital
- the Guangdong Medical University Students’ Innovation and Entrepreneurship Training Program
- the Provincial and National College Students’ Innovation and Entrepreneurship Training Program
- the Cai Limin National Traditional Chinese Medicine Inheritance Studio
- the Guangdong Medical University Students’ Innovation Experiment Program
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Affiliation(s)
- Yikuan Du
- Central Laboratory, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, 523059, China
| | - Yuying Huo
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Yujia Yang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Peiqi Lin
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Wuzheng Liu
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Ziqin Wang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Wenqi Zeng
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Jiahui Li
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Zhonghan Liang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Chenyue Yuan
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Jinfeng Zhu
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Ziyi Luo
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China
| | - Yi Liu
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China
| | - Chunling Ma
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China
| | - Chun Yang
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China.
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23
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Vrzalova A, Vrzal R. Orchestra of ligand-activated transcription factors in the molecular symphony of SERPINE 1 / PAI-1 gene regulation. Biochimie 2025; 228:138-157. [PMID: 39321911 DOI: 10.1016/j.biochi.2024.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 09/04/2024] [Accepted: 09/20/2024] [Indexed: 09/27/2024]
Abstract
Plasminogen activator inhibitor 1 (PAI-1) is a crucial serine protease inhibitor that prevents plasminogen activation by inhibiting tissue- and urokinase-type plasminogen activators (tPA, uPA). PAI-1 is well-known for its role in modulating hemocoagulation or extracellular matrix formation by inhibiting plasmin or matrix metalloproteinases, respectively. PAI-1 is induced by pro-inflammatory cytokines across various tissues, yet its regulation by ligand-activated transcription factors is partly disregarded. Therefore, we have attempted to summarize the current knowledge on the transcriptional regulation of PAI-1 expression by the most relevant xenobiotic and endocrine receptors implicated in modulating PAI-1 levels. This review aims to contribute to the understanding of the specific, often tissue-dependent regulation of PAI-1 and provide insights into the modulation of PAI-1 levels beyond its direct inhibition.
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Affiliation(s)
- Aneta Vrzalova
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic
| | - Radim Vrzal
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
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24
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Mann JP, Tábara LC, Patel S, Pushpa P, Alvarez-Guaita A, Dong L, Haider A, Lim K, Tandon P, Scurria F, Minchin JEN, O’Rahilly S. S, Fazakerley DJ, Prudent J, Semple RK, Savage DB. Loss of Mfn1 but not Mfn2 enhances adipogenesis. PLoS One 2024; 19:e0306243. [PMID: 39739772 PMCID: PMC11687706 DOI: 10.1371/journal.pone.0306243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 06/13/2024] [Indexed: 01/02/2025] Open
Abstract
OBJECTIVE A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells. METHODS We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA. RESULTS Mfn1-/- MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile including Pparg upregulation. Mfn2-/- MEFs also had a disrupted mitochondrial morphology, but in contrast to Mfn1-/- MEFs they showed reduced expression of adipocyte markers. Mfn1 and Mfn2 siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings. CONCLUSIONS Loss of Mfn1 but not Mfn2 in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.
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Affiliation(s)
- Jake P. Mann
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Luis Carlos Tábara
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
| | - Satish Patel
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Pushpa Pushpa
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Anna Alvarez-Guaita
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Liang Dong
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Afreen Haider
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Koini Lim
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Panna Tandon
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Fabio Scurria
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - James E. N. Minchin
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Stephen O’Rahilly S.
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Daniel J. Fazakerley
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Julien Prudent
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
| | - Robert K. Semple
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
- MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom
| | - David B. Savage
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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Sorokina M, Bobkov D, Khromova N, Vilchinskaya N, Shenkman B, Kostareva A, Dmitrieva R. Fibro-adipogenic progenitor cells in skeletal muscle unloading: metabolic and functional impairments. Skelet Muscle 2024; 14:31. [PMID: 39639402 PMCID: PMC11622572 DOI: 10.1186/s13395-024-00362-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 11/20/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Skeletal muscle resident fibro-adipogenic progenitor cells (FAPs) control skeletal muscle regeneration providing a supportive role for muscle stem cells. Altered FAPs characteristics have been shown for a number of pathological conditions, but the influence of temporary functional unloading of healthy skeletal muscle on FAPs remains poorly studied. This work is aimed to investigate how skeletal muscle disuse affects the functionality and metabolism of FAPs. METHODS Hindlimb suspension (HS) rat model employed to investigate muscle response to decreased usage. FAPs were purified from m. soleus functioning muscle (Contr) and after functional unloading for 7 and 14 days (HS7 and HS14). FAPs were expanded in vitro, and tested for: immunophenotype; in vitro expansion rate, and migration activity; ability to differentiate into adipocytes in vitro; metabolic changes. Crosstalk between FAPs and muscle stem cells was estimated by influence of medium conditioned by FAP's on migration and myogenesis of C2C12 myoblasts. To reveal the molecular mechanisms behind unloading-induced alterations in FAP's functionality transcriptome analysis was performed. RESULTS FAPs isolated from Contr and HS muscles exhibited phenotype of MSC cells. FAPs in vitro expansion rate and migration were altered by functional unloading conditions. All samples of FAPs demonstrated the ability to adipogenic differentiation in vitro, however, HS FAPs formed fat droplets of smaller volume and transcriptome analysis showed fatty acids metabolism and PPAR signaling suppression. Skeletal muscle unloading resulted in metabolic reprogramming of FAPs: decreased spare respiratory capacity, decreased OCR/ECAR ratio detected in both HS7 and HS14 samples point to reduced oxygen consumption, decreased potential for substrate oxidation and a shift to glycolytic metabolism. Furthermore, C2C12 cultures treated with medium conditioned by FAPs showed diverse alterations: while the HS7 FAPs-derived paracrine factors supported the myoblasts fusion, the HS14-derived medium stimulated proliferation of C2C12 myoblasts; these observations were supported by increased expression of cytokines detected by transcriptome analysis. CONCLUSION the results obtained in this work show that the skeletal muscle functional unloading affects properties of FAPs in time-dependent manner: in atrophying skeletal muscle FAPs act as the sensors for the regulatory signals that may stimulate the metabolic and transcriptional reprogramming to preserve FAPs properties associated with maintenance of skeletal muscle homeostasis during unloading and in course of rehabilitation.
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Affiliation(s)
| | - Danila Bobkov
- Almazov National Medical Research Centre, Saint Petersburg, Russia
- Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, Russia
| | - Natalia Khromova
- Almazov National Medical Research Centre, Saint Petersburg, Russia
| | | | - Boris Shenkman
- Myology Laboratory, Institute of Biomedical Problems RAS, Moscow, Russia
| | - Anna Kostareva
- Almazov National Medical Research Centre, Saint Petersburg, Russia
- Department of Women's and Children's Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Renata Dmitrieva
- Almazov National Medical Research Centre, Saint Petersburg, Russia.
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26
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Boczki P, Colombo M, Weiner J, Rapöhn I, Lacher M, Kiess W, Hanschkow M, Körner A, Landgraf K. Inhibition of AHCY impedes proliferation and differentiation of mouse and human adipocyte progenitor cells. Adipocyte 2024; 13:2290218. [PMID: 38064408 PMCID: PMC10732623 DOI: 10.1080/21623945.2023.2290218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
S-adenosyl-homocysteine-hydrolase (AHCY) plays an important role in the methionine cycle regulating cellular methylation levels. AHCY has been reported to influence proliferation and differentiation processes in different cell types, e.g. in cancer cells and mouse embryonic stem cells. In the development of adipose tissue, both the proliferation and differentiation of adipocyte progenitor cells (APCs) are important processes, which in the context of obesity are often dysregulated. To assess whether AHCY might also be involved in cell proliferation and differentiation of APCs, we investigated the effect of reduced AHCY activity on human and mouse APCs in vitro. We show that the inhibition of AHCY using adenosine dialdehyde (AdOx) and the knockdown of AHCY using gene-specific siRNAs reduced APC proliferation and number. Inhibition of AHCY further reduced APC differentiation into mature adipocytes and the expression of adipogenic differentiation markers. Global DNA methylation profiling in human APCs revealed that inhibition of AHCY is associated with alterations in CpG methylation levels of genes involved in fat cell differentiation and pathways related to cellular growth. Our findings suggest that AHCY is necessary for the maintenance of APC proliferation and differentiation and inhibition of AHCY alters DNA methylation processes leading to a dysregulation of the expression of genes involved in the regulation of these processes.
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Affiliation(s)
- Paula Boczki
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
| | - Marco Colombo
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
| | - Juliane Weiner
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
| | - Inka Rapöhn
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Martin Lacher
- Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany
| | - Wieland Kiess
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
| | - Martha Hanschkow
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
| | - Antje Körner
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Kathrin Landgraf
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
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Zhang H, Wague A, Diaz A, Liu M, Sang L, Youn A, Sharma S, Milan N, Kim H, Feeley B, Liu X. Overexpression of PRDM16 improves muscle function after rotator cuff tears. J Shoulder Elbow Surg 2024; 33:2725-2733. [PMID: 39032686 PMCID: PMC12070449 DOI: 10.1016/j.jse.2024.05.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 05/01/2024] [Accepted: 05/19/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND Muscle atrophy, fibrosis, and fatty infiltration are commonly seen in rotator cuff tears (RCTs), which are critical factors that directly determine the clinical outcomes for patients with this injury. Therefore, improving muscle quality after RCT is crucial in improving the clinical outcome of tendon repair. In recent years, it has been discovered that adults have functional beige/brown adipose tissue (BAT) that can secrete batokines to promote muscle growth. PRDM16, a PR-domain-containing protein, was discovered with the ability to determine the brown fat cell fate and stimulate its development. Thus, the goal of this study was to discover the role of PRDM16 in improving muscle function after massive tendon tears using a transgenic mouse model with an elevated level of PRDM16 expression. METHODS Transgenic aP2-driven PRDM16-overexpressing mice and C57BL/6J mice underwent unilateral supraspinatus (SS) tendon transection and suprascapular nerve transection (TTDN) as described previously (n = 8 in each group). DigiGait was performed to evaluate forelimb function at 6 weeks post the TTDN injury. Bilateral SS muscles, interscapular brown fat, epididymal white fat, and inguinal beige fat were harvested for analysis. The expression of PRDM16 in adipose tissue was detected by Western blot. Masson Trichrome staining was conducted to evaluate the muscle fibrosis, and Oil Red O staining was used to determine the fat infiltration. Muscle fiber type was determined by major histocompatibility complex (MHC) expression via immunostaining. All data were presented in the form of mean ± standard deviation. t test and 2-way analysis of variance was performed to determine a statistically significant difference between groups. Significance was considered when P < .05. RESULTS Western blot data showed an increased expression of PRDM16 protein in both white and brown fat in PRDM16-overexpressing mice compared with wild-type (WT) mice. Even though PRDM16 overexpression had no effect on increasing muscle weight, it significantly improved the forelimbs function with longer brake, stance, and stride time and larger stride length and paw area in mice after RCT. Additionally, PRDM16-overexpressing mice showed no difference in the amount of fibrosis when compared to WT mice; however, they had a significantly reduced area of fatty infiltration. These mice also exhibited abundant MHC-IIx fiber percentage in the supraspinatus muscle after TTDN. CONCLUSION Overexpression of PRDM16 significantly improved muscle function and reduced fatty infiltration after rotator cuff tears. Promoting BAT activity is beneficial in improving rotator cuff muscle quality and shoulder function after RCT.
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Affiliation(s)
- He Zhang
- Department of Physical Education, Central South University, Changsha, Hunan, China; Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Aboubacar Wague
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Agustin Diaz
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Mengyao Liu
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Luke Sang
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Alex Youn
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Sankalp Sharma
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Nesa Milan
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Hubert Kim
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Brian Feeley
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Xuhui Liu
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA.
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Amuso VM, Haas MR, Cooper PO, Chatterjee R, Hafiz S, Salameh S, Gohel C, Mazumder MF, Josephson V, Kleb SS, Khorsandi K, Horvath A, Rahnavard A, Shook BA. Fibroblast-Mediated Macrophage Recruitment Supports Acute Wound Healing. J Invest Dermatol 2024:S0022-202X(24)02956-7. [PMID: 39581458 DOI: 10.1016/j.jid.2024.10.609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 10/28/2024] [Accepted: 10/30/2024] [Indexed: 11/26/2024]
Abstract
Epithelial and immune cells have long been appreciated for their contribution to the early immune response after injury; however, much less is known about the role of mesenchymal cells. Using single-nuclei RNA sequencing, we defined changes in gene expression associated with inflammation 1 day after wounding in mouse skin. Compared with those in keratinocytes and myeloid cells, we detected enriched expression of proinflammatory genes in fibroblasts associated with deeper layers of the skin. In particular, SCA1+ fibroblasts were enriched for numerous chemokines, including CCL2, CCL7, and IL-33, compared with SCA1- fibroblasts. Genetic deletion of Ccl2 in fibroblasts resulted in fewer wound-bed macrophages and monocytes during injury-induced inflammation, with reduced revascularization and re-epithelialization during the proliferation phase of healing. These findings highlight the important contribution of fibroblast-derived factors to injury-induced inflammation and the impact of immune cell dysregulation on subsequent tissue repair.
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Affiliation(s)
- Veronica M Amuso
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - MaryEllen R Haas
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Paula O Cooper
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Ranojoy Chatterjee
- Computational Biology Institute, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, District of Columbia, USA
| | - Sana Hafiz
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Shatha Salameh
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Chiraag Gohel
- Computational Biology Institute, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, District of Columbia, USA
| | - Miguel F Mazumder
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Violet Josephson
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Sarah S Kleb
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Khatereh Khorsandi
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Anelia Horvath
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Ali Rahnavard
- Computational Biology Institute, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, District of Columbia, USA
| | - Brett A Shook
- The Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA; The Department of Dermatology, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
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29
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Plissonneau C, Santosa S. Regional primary preadipocyte characteristics in humans with obesity and type 2 diabetes mellitus. Heliyon 2024; 10:e39710. [PMID: 39553621 PMCID: PMC11564010 DOI: 10.1016/j.heliyon.2024.e39710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 10/21/2024] [Accepted: 10/21/2024] [Indexed: 11/19/2024] Open
Abstract
The excessive accumulation of adipose tissue in obesity appears to result in adipose tissue dysfunction perpetuating the onset of obesity-related diseases, including type 2 diabetes (T2DM). In humans, adipose tissue is stored in several depots including subcutaneous and visceral. These depots contribute to the pathology of obesity differently owing to differences in the tissue microenvironment, a main one being preadipocyte function. In examining adipocyte and preadipocyte characteristics, many have used the 3T3-L1 murine cell lines. Though these cell lines provide valuable mechanistic data, the results remain to be translated to humans. Experiments using primary human preadipocytes has shown that obesity and T2DM impact preadipocyte phenotypes. The objective of this review is to describe the differences in regional characteristics of primary preadipocytes collected from humans with obesity and to discuss how these characteristics might be affected in type 2 diabetes mellitus. In doing so, we will show that the characteristics of regional primary preadipocytes in humans are differentially affected by obesity and the development of T2DM.
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Affiliation(s)
- Claire Plissonneau
- Department of Health, Kinesiology, and Applied Physiology, Concordia University, Montreal, Quebec, Canada
- Metabolism, Obesity, and Nutrition Lab, School of Health, Concordia University, Montreal, Quebec, Canada
- Centre de recherche - Axe maladies chroniques, Centre intégré universitaire de santé et de services sociaux du Nord-de-l'Ile-de-Montréal, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada
| | - Sylvia Santosa
- Department of Health, Kinesiology, and Applied Physiology, Concordia University, Montreal, Quebec, Canada
- Metabolism, Obesity, and Nutrition Lab, School of Health, Concordia University, Montreal, Quebec, Canada
- Centre de recherche - Axe maladies chroniques, Centre intégré universitaire de santé et de services sociaux du Nord-de-l'Ile-de-Montréal, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada
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Hossain MN, Gao Y, Li X, Zhao L, Liu X, Marie de Avila J, Zhu MJ, Du M. Single-cell RNA transcriptomics in mice reveals embryonic origin of fibrosis due to maternal obesity. EBioMedicine 2024; 109:105421. [PMID: 39476533 PMCID: PMC11565040 DOI: 10.1016/j.ebiom.2024.105421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Over 40% of pregnant women in the USA are obese which negatively affects fetal development and offspring health. Maternal obesity (MO) leads to fibrotic infiltration in multiple tissues and organs of offspring during their adulthood although the origin and mechanisms are unclear. METHODS C57BL/6J female mice were fed a control and high-fat diet to mimic MO condition. Embryonic somatic tissues were obtained at E9.5, E11.5, and E13.5 (equivalent to 6 weeks of human pregnancy) from control (CON) and MO mice for single-cell RNA-sequencing (scRNA-seq). To explore the role of AMP-activated protein kinase (AMPK), AMPK was activated by metformin and A769662, and knocked out in embryonic mesenchymal cells (EMC) using AMPKα1 floxed mice. FINDINGS Using unsupervised clustering, we identified three major cell populations with fibrogenic capacity. Compared to CON, the population of fibrogenic cells increased dramatically (by ∼125%) due to MO, supporting an embryonic origin of fibrosis in the offspring. MO induced inflammatory response and elevated expression of transforming growth factor β (TGFβ) signalling and fibrogenic genes in embryos. MO inhibited AMPK and its activation by metformin and A769662 inhibited TGFβ signalling and fibrogenesis. INTERPRETATION MO profoundly enhances embryonic fibrogenesis, explaining the origin of fibrosis in the offspring of mothers living with obesity. Our data underscore the importance of early intervention, before 5-6 weeks of pregnancy, in improving embryonic development, and AMPK is an amiable target for suppressing excessive fibrogenesis in MO embryos to assist increasing populations of obese mothers having healthy children. FUNDING This work was funded by National Institutes of Health Grant R01HD067449.
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Affiliation(s)
- Md Nazmul Hossain
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, 99164, USA
| | - Yao Gao
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, 99164, USA
| | - Xinrui Li
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, 99164, USA
| | - Liang Zhao
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, 99164, USA; College of Animal Science and Technology, Nanjing Agricultural University, China
| | - Xiangdong Liu
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, 99164, USA; Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA
| | - Jeanene Marie de Avila
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, 99164, USA
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA, 99164, USA
| | - Min Du
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, 99164, USA.
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Bérubé R, Murray B, Kocarek TA, Gurdziel K, Kassotis CD. Nonylphenol and Cetyl Alcohol Polyethoxylates Disrupt Thyroid Hormone Receptor Signaling to Disrupt Metabolic Health. Endocrinology 2024; 165:bqae149. [PMID: 39497475 PMCID: PMC11574291 DOI: 10.1210/endocr/bqae149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/08/2024]
Abstract
Surfactants are molecules with both hydrophobic and hydrophilic structural groups that adsorb at the air-water or oil-water interface and serve to decrease the surface tension. Surfactants combine to form micelles that surround and break down or remove oils, making them ideal for detergents and cleaners. Two of the most important classes of nonionic surfactants are alkylphenol ethoxylates (APEOs) and alcohol ethoxylates (AEOs). APEOs and AEOs are high production-volume chemicals that are used for many industrial and residential purposes, including laundry detergents, hard-surface cleaners, paints, and pesticide adjuvants. Commensurate with better appreciation of the toxicity of APEOs and the base alkylphenols, use of AEOs has increased, and both sets of compounds are now ubiquitous environmental contaminants. We recently demonstrated that diverse APEOs and AEOs induce triglyceride accumulation and/or preadipocyte proliferation in vitro. Both sets of contaminants have also been demonstrated as obesogenic and metabolism-disrupting in a developmental exposure zebrafish model. While these metabolic health effects are consistent across models and species, the mechanisms underlying these effects are less clear. This study sought to evaluate causal mechanisms through reporter gene assays, relative binding affinity assays, coexposure experiments, and use of both human cell and zebrafish models. We report that antagonism of thyroid hormone receptor signaling appears to mediate at least a portion of the polyethoxylate-induced metabolic health effects. These results suggest further evaluation is needed, given the ubiquitous environmental presence of these thyroid-disrupting contaminants and reproducible effects in human cell models and vertebrate animals.
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Affiliation(s)
- Roxanne Bérubé
- Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, USA
| | - Brooklynn Murray
- Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, USA
| | - Thomas A Kocarek
- Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, USA
| | - Katherine Gurdziel
- Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, USA
- Genome Sciences Core, Wayne State University, Detroit, MI 48202, USA
| | - Christopher D Kassotis
- Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, USA
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Sun L, Liu X, Du J, Yang H, Lin Y, Yu D, Li C, Zheng Y. Adipogenic Effects of Cresyl Diphenyl Phosphate (Triphenyl Phosphate Alternative) through Peroxisome Proliferator-Activated Receptor Gamma Pathway: A Comprehensive Study Integrating In Vitro, In Vivo, and In Silico from Molecule to Health Risk. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:18631-18641. [PMID: 39382118 DOI: 10.1021/acs.est.4c07215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
Cresyl diphenyl phosphate (CDP), a novel organophosphate ester (OPE), has been detected in various environmental and human samples. However, there is very limited knowledge regarding its toxicity, mechanisms of action, and potential health risks. Using new alternative methods (NAMs), across the molecular interactions, signaling pathways, cell functions, animal effects, and population risks, we investigated the potential adipogenic effects and associated risks of CDP and legacy OPE triphenyl phosphate (TPHP) by acting on peroxisome proliferator-activated receptor gamma (PPARγ). Among the 19 screened OPEs, CDP bound to PPARγ with the highest binding potency, followed by TPHP. CDP activated PPARγ through fitting into the binding pocket with strong hydrophobicity and hydrogen bond interactions; CDP exhibited higher potency compared to TPHP. In 3T3-L1 cells, CDP enhanced the PPARγ-mediated adipogenesis activity, exhibiting greater potency than TPHP. The intracellular concentration and receptor-bound concentrations (RBC) of CDP were also higher than those of TPHP in both HEK293 cells and 3T3-L1 cells. In mice, exposure to CDP activated the PPARγ-mediated adipogenic pathway, leading to an increased white adipose tissue weight gain. Overall, CDP could bind to and activate PPARγ, thereby promoting preadipocyte differentiation and the development of white adipose tissue. Its potential obesogenic risks should be of high concern.
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Affiliation(s)
- Lanchao Sun
- School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China
| | - Xinya Liu
- School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China
| | - Jingyue Du
- School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China
| | - Huizi Yang
- School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China
| | - Yongfeng Lin
- School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China
| | - Dianke Yu
- School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China
| | - Chuanhai Li
- School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China
| | - Yuxin Zheng
- School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China
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Pinette JA, Myers JW, Park WY, Bryant HG, Eddie AM, Wilson GA, Montufar C, Shaikh Z, Vue Z, Nunn ER, Bessho R, Cottam MA, Haase VH, Hinton AO, Spinelli JB, Cartailler JP, Zaganjor E. Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis. J Lipid Res 2024; 65:100641. [PMID: 39245323 PMCID: PMC11913791 DOI: 10.1016/j.jlr.2024.100641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/13/2024] [Accepted: 08/27/2024] [Indexed: 09/10/2024] Open
Abstract
A key organismal response to overnutrition involves the development of new adipocytes through the process of adipogenesis. Preadipocytes sense changes in the systemic nutrient status and metabolites can directly modulate adipogenesis. We previously identified a role of de novo nucleotide biosynthesis in adipogenesis induction, whereby inhibition of nucleotide biosynthesis suppresses the expression of the transcriptional regulators PPARγ and C/EBPα. Here, we set out to identify the global transcriptomic changes associated with the inhibition of nucleotide biosynthesis. Through RNA sequencing (RNAseq), we discovered that mitochondrial signatures were the most altered in response to inhibition of nucleotide biosynthesis. Blocking nucleotide biosynthesis induced rounded mitochondrial morphology, and altered mitochondrial function, and metabolism, reducing levels of tricarboxylic acid cycle intermediates, and increasing fatty acid oxidation (FAO). The loss of mitochondrial function induced by suppression of nucleotide biosynthesis was rescued by exogenous expression of PPARγ. Moreover, inhibition of FAO restored PPARγ expression, mitochondrial protein expression, and adipogenesis in the presence of nucleotide biosynthesis inhibition, suggesting a regulatory role of nutrient oxidation in differentiation. Collectively, our studies shed light on the link between substrate oxidation and transcription in cell fate determination.
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Affiliation(s)
- Julia A Pinette
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Jacob W Myers
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Woo Yong Park
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Heather G Bryant
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Alex M Eddie
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Genesis A Wilson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Claudia Montufar
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Zayedali Shaikh
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Zer Vue
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Elizabeth R Nunn
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Ryoichi Bessho
- Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Matthew A Cottam
- Creative Data Solutions, Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA
| | - Volker H Haase
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Research and Medical Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Antentor O Hinton
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Jessica B Spinelli
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jean-Philippe Cartailler
- Creative Data Solutions, Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA
| | - Elma Zaganjor
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Diabetes Research Center, Vanderbilt University, Nashville, TN, USA.
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Szychowski KA, Skóra B. Elastin-derived peptides (EDPs) affect gene and protein expression in human mesenchymal stem cells (hMSCs) - preliminary study. Cytokine 2024; 182:156725. [PMID: 39106575 DOI: 10.1016/j.cyto.2024.156725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/25/2024] [Accepted: 08/01/2024] [Indexed: 08/09/2024]
Abstract
During the aging process, elastin is degraded and the level of elastin-derived peptides (EDPs) successively increases. The main peptide released from elastin during its degradation is a peptide with the VGVAPG sequence. To date, several papers have described that EDPs or elastin-like peptides (ELPs) affect human mesenchymal stem cells (hMSCs) derived from different tissues. Unfortunately, despite the described effect of EDPs or ELPs on the hMSC differentiation process, the mechanism of action of these peptides has not been elucidated. Therefore, the aim of the present study was to evaluate the impact of the VGVAPG and VVGPGA peptides on the hMSC stemness marker and elucidation of the mechanism of action of these peptides. Our data show that both studied peptides (VGVAPG and VVGPGA) act with the involvement of ERK1/2 and c-SRC kinases. However, their mechanism of activation is probably different in hMSCs derived from adipose tissue. Both studied peptides increase the KI67 protein level in hMSCs, but this is not accompanied with cell proliferation. Moreover, the changes in the NANOG and c-MYC protein expression and in the SOX2 and POU5F1 mRNA expression suggest that EDPs reduced the hMSC stemness properties and could initiate cell differentiation. The initiation of differentiation was evidenced by changes in the expression of AhR and PPARγ protein as well as specific genes (ACTB, TUBB3) and proteins (β-actin, RhoA) involved in cytoskeleton remodeling. Our data suggest that the presence of EDPs in tissue can initiate hMSC differentiation into more tissue-specific cells.
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Affiliation(s)
- Konrad A Szychowski
- Department of Biotechnology and Cell Biology, Medical College, University of Information Technology and Management in Rzeszow, St. Sucharskiego 2, 35-225 Rzeszow, Poland.
| | - Bartosz Skóra
- Department of Biotechnology and Cell Biology, Medical College, University of Information Technology and Management in Rzeszow, St. Sucharskiego 2, 35-225 Rzeszow, Poland
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Mao L, Lu J, Hou Y, Nie T. Directly targeting PRDM16 in thermogenic adipose tissue to treat obesity and its related metabolic diseases. Front Endocrinol (Lausanne) 2024; 15:1458848. [PMID: 39351529 PMCID: PMC11439700 DOI: 10.3389/fendo.2024.1458848] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 08/28/2024] [Indexed: 10/04/2024] Open
Abstract
Obesity is increasing globally and is closely associated with a range of metabolic disorders, including metabolic associated fatty liver disease, diabetes, and cardiovascular diseases. An effective strategy to combat obesity involves stimulating brown and beige adipocyte thermogenesis, which significantly enhances energy expenditure. Recent research has underscored the vital role of PRDM16 in the development and functionality of thermogenic adipocytes. Consequently, PRDM16 has been identified as a potential therapeutic target for obesity and its related metabolic disorders. This review comprehensively examines various studies that focus on combating obesity by directly targeting PRDM16 in adipose tissue.
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Affiliation(s)
- Liufeng Mao
- The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jinli Lu
- The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yunliang Hou
- The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China
| | - Tao Nie
- School of Basic Medicine, Hubei University of Arts and Science, Xiangyang, China
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Anaya ES, de Groot EL, Lydon JP, Pangas SA, Hartig SM. Contributions of white adipose tissue to energy requirements for female reproduction. Trends Endocrinol Metab 2024; 35:809-820. [PMID: 38749883 PMCID: PMC11387141 DOI: 10.1016/j.tem.2024.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/13/2024] [Accepted: 04/15/2024] [Indexed: 09/12/2024]
Abstract
Body composition impacts female fertility and there are established relationships between adipose tissue and the reproductive system. Maintaining functional adipose tissue is vital for meeting the energetic demands during the reproductive process, from ovulation to delivery and lactation. White adipose tissue (WAT) shows plastic responses to daily physiology and secretes diverse adipokines that affect the hypothalamic-pituitary-ovarian axis, but many other interorgan interactions remain to be determined. This review summarizes the current state of research on the dialogue between WAT and the female reproductive system, focusing on the impact of this crosstalk on ovarian and endometrial factors essential for fecundity.
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Affiliation(s)
- Elizabeth S Anaya
- Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Cancer and Cellular Biology Program, Baylor College of Medicine, Houston, TX, USA
| | - Evelyn L de Groot
- Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Cancer and Cellular Biology Program, Baylor College of Medicine, Houston, TX, USA
| | - John P Lydon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Stephanie A Pangas
- Cancer and Cellular Biology Program, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Sean M Hartig
- Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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Ahmad N, Anker A, Klein S, Dean J, Knoedler L, Remy K, Pagani A, Kempa S, Terhaag A, Prantl L. Autologous Fat Grafting-A Panacea for Scar Tissue Therapy? Cells 2024; 13:1384. [PMID: 39195271 PMCID: PMC11352477 DOI: 10.3390/cells13161384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 08/04/2024] [Accepted: 08/05/2024] [Indexed: 08/29/2024] Open
Abstract
Scars may represent more than a cosmetic concern for patients; they may impose functional limitations and are frequently associated with the sensation of itching or pain, thus impacting both psychological and physical well-being. From an aesthetic perspective, scars display variances in color, thickness, texture, contour, and their homogeneity, while the functional aspect encompasses considerations of functionality, pliability, and sensory perception. Scars located in critical anatomic areas have the potential to induce profound impairments, including contracture-related mobility restrictions, thereby significantly impacting daily functioning and the quality of life. Conventional approaches to scar management may suffice to a certain extent, yet there are cases where tailored interventions are warranted. Autologous fat grafting emerges as a promising therapeutic avenue in such instances. Fundamental mechanisms underlying scar formation include chronic inflammation, fibrogenesis and dysregulated wound healing, among other contributing factors. These mechanisms can potentially be alleviated through the application of adipose-derived stem cells, which represent the principal cellular component utilized in the process of lipofilling. Adipose-derived stem cells possess the capacity to secrete proangiogenic factors such as fibroblast growth factor, vascular endothelial growth factor and hepatocyte growth factor, as well as neurotrophic factors, such as brain-derived neurotrophic factors. Moreover, they exhibit multipotency, remodel the extracellular matrix, act in a paracrine manner, and exert immunomodulatory effects through cytokine secretion. These molecular processes contribute to neoangiogenesis, the alleviation of chronic inflammation, and the promotion of a conducive milieu for wound healing. Beyond the obvious benefit in restoring volume, the adipose-derived stem cells and their regenerative capacities facilitate a reduction in pain, pruritus, and fibrosis. This review elucidates the regenerative potential of autologous fat grafting and its beneficial and promising effects on both functional and aesthetic outcomes when applied to scar tissue.
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Affiliation(s)
- Nura Ahmad
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz–Josef–Strauß Allee 11, 93053 Regensburg, Germany; (A.A.); (S.K.); (L.K.); (A.P.); (S.K.); (A.T.); (L.P.)
| | - Alexandra Anker
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz–Josef–Strauß Allee 11, 93053 Regensburg, Germany; (A.A.); (S.K.); (L.K.); (A.P.); (S.K.); (A.T.); (L.P.)
| | - Silvan Klein
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz–Josef–Strauß Allee 11, 93053 Regensburg, Germany; (A.A.); (S.K.); (L.K.); (A.P.); (S.K.); (A.T.); (L.P.)
| | - Jillian Dean
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA;
| | - Leonard Knoedler
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz–Josef–Strauß Allee 11, 93053 Regensburg, Germany; (A.A.); (S.K.); (L.K.); (A.P.); (S.K.); (A.T.); (L.P.)
| | - Katya Remy
- Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - Andrea Pagani
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz–Josef–Strauß Allee 11, 93053 Regensburg, Germany; (A.A.); (S.K.); (L.K.); (A.P.); (S.K.); (A.T.); (L.P.)
| | - Sally Kempa
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz–Josef–Strauß Allee 11, 93053 Regensburg, Germany; (A.A.); (S.K.); (L.K.); (A.P.); (S.K.); (A.T.); (L.P.)
| | - Amraj Terhaag
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz–Josef–Strauß Allee 11, 93053 Regensburg, Germany; (A.A.); (S.K.); (L.K.); (A.P.); (S.K.); (A.T.); (L.P.)
| | - Lukas Prantl
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz–Josef–Strauß Allee 11, 93053 Regensburg, Germany; (A.A.); (S.K.); (L.K.); (A.P.); (S.K.); (A.T.); (L.P.)
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Amuso VM, Haas MR, Cooper PO, Chatterjee R, Hafiz S, Salameh S, Gohel C, Mazumder MF, Josephson V, Khorsandi K, Horvath A, Rahnavard A, Shook BA. Deep skin fibroblast-mediated macrophage recruitment supports acute wound healing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.09.607357. [PMID: 39149286 PMCID: PMC11326280 DOI: 10.1101/2024.08.09.607357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Epithelial and immune cells have long been appreciated for their contribution to the early immune response after injury; however, much less is known about the role of mesenchymal cells. Using single nuclei RNA-sequencing, we defined changes in gene expression associated with inflammation at 1-day post-wounding (dpw) in mouse skin. Compared to keratinocytes and myeloid cells, we detected enriched expression of pro-inflammatory genes in fibroblasts associated with deeper layers of the skin. In particular, SCA1+ fibroblasts were enriched for numerous chemokines, including CCL2, CCL7, and IL33 compared to SCA1- fibroblasts. Genetic deletion of Ccl2 in fibroblasts resulted in fewer wound bed macrophages and monocytes during injury-induced inflammation with reduced revascularization and re-epithelialization during the proliferation phase of healing. These findings highlight the important contribution of deep skin fibroblast-derived factors to injury-induced inflammation and the impact of immune cell dysregulation on subsequent tissue repair.
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Affiliation(s)
- Veronica M. Amuso
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - MaryEllen R. Haas
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - Paula O. Cooper
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - Ranojoy Chatterjee
- Computational Biology Institute, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC 20052, USA
| | - Sana Hafiz
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - Shatha Salameh
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - Chiraag Gohel
- Computational Biology Institute, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC 20052, USA
| | - Miguel F. Mazumder
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - Violet Josephson
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - Khatereh Khorsandi
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - Anelia Horvath
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - Ali Rahnavard
- Computational Biology Institute, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC 20052, USA
| | - Brett A. Shook
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
- Department of Dermatology, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
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Yoshida J, Hayashi T, Munetsuna E, Khaledian B, Sueishi F, Mizuno M, Maeda M, Watanabe T, Ushida K, Sugihara E, Imaizumi K, Kawada K, Asai N, Shimono Y. Adipsin-dependent adipocyte maturation induces cancer cell invasion in breast cancer. Sci Rep 2024; 14:18494. [PMID: 39122742 PMCID: PMC11316094 DOI: 10.1038/s41598-024-69476-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024] Open
Abstract
Adipocyte-cancer cell interactions promote tumor development and progression. Previously, we identified adipsin (CFD) and its downstream effector, hepatocyte growth factor (HGF), as adipokines that enhance adipocyte-breast cancer stem cell interactions. Here, we show that adipsin-dependent adipocyte maturation and the subsequent upregulation of HGF promote tumor invasion in breast cancers. Mature adipocytes, but not their precursors, significantly induced breast tumor cell migration and invasion in an adipsin expression-dependent manner. Promoters of tumor invasion, galectin 7 and matrix metalloproteinases, were significantly upregulated in cancer cells cocultured with mature adipocytes; meanwhile, their expression levels in cancer cells cocultured with adipocytes were reduced by adipsin knockout (Cfd KO) or a competitive inhibitor of CFD. Tumor growth and distant metastasis of mammary cancer cells were significantly suppressed when syngeneic mammary cancer cells were transplanted into Cfd KO mice. Histological analyses revealed reductions in capsular formation and tumor invasion at the cancer-adipocyte interface in the mammary tumors formed in Cfd KO mice. These findings indicate that adipsin-dependent adipocyte maturation may play an important role in adipocyte-cancer cell interaction and breast cancer progression.
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Affiliation(s)
- Jumpei Yoshida
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
- Department of Medical Oncology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Takanori Hayashi
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Behnoush Khaledian
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Fujiko Sueishi
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Masahiro Mizuno
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
| | - Masao Maeda
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Takashi Watanabe
- Division of Gene Regulation, Oncology Innovation Center, Fujita Health University, Toyoake, Aichi, 4701192, Japan
| | - Kaori Ushida
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Eiji Sugihara
- Division of Gene Regulation, Oncology Innovation Center, Fujita Health University, Toyoake, Aichi, 4701192, Japan
| | - Kazuyoshi Imaizumi
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Kenji Kawada
- Department of Medical Oncology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Naoya Asai
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Yohei Shimono
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 4701192, Japan.
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Dowker-Key PD, Jadi PK, Gill NB, Hubbard KN, Elshaarrawi A, Alfatlawy ND, Bettaieb A. A Closer Look into White Adipose Tissue Biology and the Molecular Regulation of Stem Cell Commitment and Differentiation. Genes (Basel) 2024; 15:1017. [PMID: 39202377 PMCID: PMC11353785 DOI: 10.3390/genes15081017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/26/2024] [Accepted: 07/28/2024] [Indexed: 09/03/2024] Open
Abstract
White adipose tissue (WAT) makes up about 20-25% of total body mass in healthy individuals and is crucial for regulating various metabolic processes, including energy metabolism, endocrine function, immunity, and reproduction. In adipose tissue research, "adipogenesis" is commonly used to refer to the process of adipocyte formation, spanning from stem cell commitment to the development of mature, functional adipocytes. Although, this term should encompass a wide range of processes beyond commitment and differentiation, to also include other stages of adipose tissue development such as hypertrophy, hyperplasia, angiogenesis, macrophage infiltration, polarization, etc.… collectively, referred to herein as the adipogenic cycle. The term "differentiation", conversely, should only be used to refer to the process by which committed stem cells progress through distinct phases of subsequent differentiation. Recognizing this distinction is essential for accurately interpreting research findings on the mechanisms and stages of adipose tissue development and function. In this review, we focus on the molecular regulation of white adipose tissue development, from commitment to terminal differentiation, and examine key functional aspects of WAT that are crucial for normal physiology and systemic metabolic homeostasis.
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Affiliation(s)
- Presley D. Dowker-Key
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
| | - Praveen Kumar Jadi
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
| | - Nicholas B. Gill
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
| | - Katelin N. Hubbard
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
| | - Ahmed Elshaarrawi
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
| | - Naba D. Alfatlawy
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
| | - Ahmed Bettaieb
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN 37996-0840, USA
- Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996-0840, USA
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Choi JW, Park GH, Choi HJ, Lee JW, Kwon HY, Choi MY, Jeong JB. Anti‑obesity and immunostimulatory activity of Chrysosplenium flagelliferum in mouse preadipocytes 3T3‑L1 cells and mouse macrophage RAW264.7 cells. Exp Ther Med 2024; 28:315. [PMID: 38911047 PMCID: PMC11190883 DOI: 10.3892/etm.2024.12604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 05/22/2024] [Indexed: 06/25/2024] Open
Abstract
Chrysosplenium flagelliferum (CF) is known for its anti-inflammatory, antioxidant and antibacterial activities. However, there is a lack of research on its other pharmacological properties. In the present study, the bifunctional roles of CF in 3T3-L1 and RAW264.7 cells were investigated, focusing on its anti-obesity and immunostimulatory effects. In 3T3-L1 cells, CF effectively mitigated the accumulation of lipid droplets and triacylglycerol. Additionally, CF downregulated the peroxisome proliferator-activated receptor (PPAR)-γ and CCAAT/enhancer-binding protein α protein levels; however, this effect was impeded by the knockdown of β-catenin using β-catenin-specific small interfering RNA. Consequently, CF-mediated inhibition of lipid accumulation was also decreased. CF increased the protein levels of adipose triglyceride lipase and phosphorylated hormone-sensitive lipase, while decreasing those of perilipin-1. Moreover, CF elevated the protein levels of phosphorylated AMP-activated protein kinase and PPARγ coactivator 1-α. In RAW264.7 cells, CF enhanced the production of pro-inflammatory mediators, such as nitric oxide (NO), inducible NO synthase, interleukin (IL)-1β, IL-6 and tumor necrosis factor-α, and increased their phagocytic capacities. Inhibition of Toll-like receptor (TLR)-4 significantly reduced the effects of CF on the production of pro-inflammatory mediators and phagocytosis, indicating its crucial role in facilitating these effects. CF-induced increase in the production of pro-inflammatory mediators was controlled by the activation of c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-κB pathways, and TLR4 inhibition attenuated the phosphorylation of these kinases. The results of the pesent study suggested that CF inhibits lipid accumulation by suppressing adipogenesis and inducing lipolysis and thermogenesis in 3T3-L1 cells, while stimulating macrophage activation via the activation of JNK and NF-κB signaling pathways mediated by TLR4 in RAW264.7 cells. Therefore, CF simultaneously exerts both anti-obesity and immunostimulatory effects.
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Affiliation(s)
- Jeong Won Choi
- Department of Forest Science, Andong National University, Andong, Gyeongsangbuk 36729, Republic of Korea
| | - Gwang Hun Park
- Forest Medicinal Resources Research Center, National Institute of Forest Science, Yeongju, Gyeongsangbuk 36040, Republic of Korea
| | - Hyeok Jin Choi
- Department of Forest Science, Andong National University, Andong, Gyeongsangbuk 36729, Republic of Korea
| | - Jae Won Lee
- Department of Forest Science, Andong National University, Andong, Gyeongsangbuk 36729, Republic of Korea
| | - Hae-Yun Kwon
- Forest Medicinal Resources Research Center, National Institute of Forest Science, Yeongju, Gyeongsangbuk 36040, Republic of Korea
| | - Min Yeong Choi
- Forest Medicinal Resources Research Center, National Institute of Forest Science, Yeongju, Gyeongsangbuk 36040, Republic of Korea
| | - Jin Boo Jeong
- Department of Forest Science, Andong National University, Andong, Gyeongsangbuk 36729, Republic of Korea
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Yang Z, Ma X, Zhang D, Li B, Gao N, Li X, Mei C, Zan L. Bta-miR-330 promotes bovine intramuscular pre-adipocytes adipogenesis via targeting SESN3 to activate the Akt-mTOR signaling pathway. Int J Biol Macromol 2024; 275:133650. [PMID: 38971288 DOI: 10.1016/j.ijbiomac.2024.133650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/31/2024] [Accepted: 06/29/2024] [Indexed: 07/08/2024]
Abstract
Consumers are more inclined to choose beef with a high intramuscular fat content (IMF), which regulated by lots of factors. It is very significant to find a miRNA that plays a key role in the accumulation of IMF. In our study, we found that bta-miR-330 was highly expressed in Japanese black cattle and differentially expressed at intramuscular pre-adipocytes differentiation processes. Furthermore, we transfected the bta-miR-330 mimic & inhibitor in intramuscular pre-adipocytes. The results showed that bta-miR-330 inhibits the proliferation but promotes the adipogenesis of intramuscular pre-adipocytes. Subsequently, our study showed that bta-miR-330 binds to SESN3, which inhibits the adipogenesis of intramuscular pre-adipocytes. Moreover, we established the mechanism that bta-miR-330 promotes the adipogenesis of intramuscular pre-adipocytes by targeting SESN3 to activate the Akt-mTOR signaling pathway. Overall, our results revealed that bta-miR-330-SESN3-Akt-mTOR axis plays an important role in adipogenesis of intramuscular pre-adipocytes, which provides a molecular basis for increasing IMF content in beef cattle.
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Affiliation(s)
- Zhimei Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Xinhao Ma
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Dianqi Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Bingzhi Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China; Yangling Vocational & Technical College, Yangling, Shaanxi 712100, PR China
| | - Ni Gao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Xuefeng Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Chugang Mei
- National Beef Cattle Improvement Center, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Linsen Zan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China; National Beef Cattle Improvement Center, Northwest A&F University, Yangling, Shaanxi 712100, PR China.
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Lei Z, Pan C, Li F, Wei D, Ma Y. SGK1 promotes the lipid accumulation via regulating the transcriptional activity of FOXO1 in bovine. BMC Genomics 2024; 25:737. [PMID: 39080526 PMCID: PMC11290151 DOI: 10.1186/s12864-024-10644-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024] Open
Abstract
OBJECTIVES Serum/glucocorticoid-inducible kinase 1 (SGK1) gene encodes a serine/threonine protein kinase that plays an essential role in cellular stress response and regulation of multiple metabolic processes. However, its role in bovine adipogenesis remains unknown. In this study, we aimed to clarify the role of SGK1 in bovine lipid accumulation and improvement of meat quality. METHODS Preadipocytes were induced to differentiation to detect the temporal expression pattern of SGK1. Heart, liver, lung, spleen, kidney, muscle and fat tissues were collected to detect its tissue expression profile. Recombinant adenovirus and the lentivirus were packaged for overexpression and knockdown. Oil Red O staining, quantitative real-time PCR, Western blot analysis, Yeast two-hybrid assay, luciferase assay and RNA-seq were performed to study the regulatory mechanism of SGK1. RESULTS SGK1 showed significantly higher expression in adipose and significantly induced expression in differentiated adipocytes. Furthermore, overexpression of SGK1 greatly promoted adipogenesis and inhibited proliferation, which could be shown by the remarkable increasement of lipid droplet, and the expression levels of adipogenic marker genes and cell cycle-related genes. Inversely, its knockdown inhibited adipogenesis and facilitated proliferation. Mechanistically, SGK1 regulates the phosphorylation and expression of two critical proteins of FoxO family, FOXO1/FOXO3. Importantly, SGK1 attenuates the transcriptional repression role of FOXO1 for PPARγ via phosphorylating the site S256, then promoting the bovine fat deposition. CONCLUSIONS SGK1 is a required epigenetic regulatory factor for bovine preadipocyte proliferation and differentiation, which contributes to a better understanding of fat deposition and meat quality improvement in cattle.
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Affiliation(s)
- Zhaoxiong Lei
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China
| | - Cuili Pan
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China
| | - Fen Li
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China
| | - Dawei Wei
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China.
| | - Yun Ma
- College of Animal Science and Technology, Ningxia University, Yinchuan, 750021, China.
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McCartney EE, Chung Y, Buechler MB. Life of Pi: Exploring functions of Pi16+ fibroblasts. F1000Res 2024; 13:126. [PMID: 38919948 PMCID: PMC11196929 DOI: 10.12688/f1000research.143511.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2024] [Indexed: 06/27/2024] Open
Abstract
Fibroblasts are mesenchymal cells that are responsible for creating and maintaining tissue architecture through the production of extracellular matrix. These cells also play critical roles in processes such as wound repair and immune modulation in normal tissues and various disease states including fibrosis, autoimmunity, and cancer. Fibroblasts have a complex repertoire of functions that vary by organ, inflammatory state, and the developmental stage of an organism. How fibroblasts manage so many functions in such a context-dependent manner represents a gap in our understanding of these cells. One possibility is that a tissue-resident precursor cell state exists that provides the fibroblast lineage with flexibility during growth, inflammation, or other contexts that require dynamic tissue changes. Recent work has suggested that a precursor fibroblast cell state is marked by expression of Peptidase inhibitor 16 ( Pi16). This review aims to concatenate and compare studies on fibroblasts that express Pi16 to clarify the roles of this cell state in fibroblast lineage development and other functions.
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Affiliation(s)
- Erika E. McCartney
- Department of Immunology, University of Toronto, Toronto, Ontario, M5S1A8, Canada
| | - Yein Chung
- Department of Immunology, University of Toronto, Toronto, Ontario, M5S1A8, Canada
| | - Matthew B. Buechler
- Department of Immunology, University of Toronto, Toronto, Ontario, M5S1A8, Canada
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Kaimala S, Lootah SS, Mehra N, Kumar CA, Marzooqi SA, Sampath P, Ansari SA, Emerald BS. The Long Non-Coding RNA Obesity-Related (Obr) Contributes To Lipid Metabolism Through Epigenetic Regulation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2401939. [PMID: 38704700 PMCID: PMC11234455 DOI: 10.1002/advs.202401939] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Indexed: 05/07/2024]
Abstract
Obesity is a multifactorial disease that is part of today's epidemic and also increases the risk of other metabolic diseases. Long noncoding RNAs (lncRNAs) provide one tier of regulatory mechanisms to maintain metabolic homeostasis. Although lncRNAs are a significant constituent of the mammalian genome, studies aimed at their metabolic significance, including obesity, are only beginning to be addressed. Here, a developmentally regulated lncRNA, termed as obesity related (Obr), whose expression in metabolically relevant tissues such as skeletal muscle, liver, and pancreas is altered in diet-induced obesity, is identified. The Clone 9 cell line and high-fat diet-induced obese Wistar rats are used as a model system to verify the function of Obr. By using stable expression and antisense oligonucleotide-mediated downregulation of the expression of Obr followed by different molecular biology experiments, its role in lipid metabolism is verified. It is shown that Obr associates with the cAMP response element-binding protein (Creb) and activates different transcription factors involved in lipid metabolism. Its association with the Creb histone acetyltransferase complex, which includes the cAMP response element-binding protein (CBP) and p300, positively regulates the transcription of genes involved in lipid metabolism. In addition, Obr is regulated by Pparγ in response to lipid accumulation.
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Affiliation(s)
- Suneesh Kaimala
- Department of Anatomy, College of Medicine and Health Sciences, UAE University, Al Ain, P.O. Box 15551, UAE
| | - Shareena Saeed Lootah
- Department of Anatomy, College of Medicine and Health Sciences, UAE University, Al Ain, P.O. Box 15551, UAE
| | - Neha Mehra
- Department of Anatomy, College of Medicine and Health Sciences, UAE University, Al Ain, P.O. Box 15551, UAE
| | - Challagandla Anil Kumar
- Department of Anatomy, College of Medicine and Health Sciences, UAE University, Al Ain, P.O. Box 15551, UAE
| | - Saeeda Al Marzooqi
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, P.O. Box 15551, UAE
| | - Prabha Sampath
- A*STAR Skin Research Laboratory, Agency for Science Technology & Research (A*STAR), Singapore, 138648, Singapore
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
- Genome Institute of Singapore, Agency for Science Technology & Research (A*STAR), Singapore, 138672, Singapore
| | - Suraiya Anjum Ansari
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, P.O. Box 15551, UAE
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, P.O. Box 15551, UAE
- ASPIRE Precision Medicine, Research Institute Abu Dhabi, Al Ain, Abu Dhabi, P.O. Box 15551, UAE
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, UAE University, Al Ain, P.O. Box 15551, UAE
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, P.O. Box 15551, UAE
- ASPIRE Precision Medicine, Research Institute Abu Dhabi, Al Ain, Abu Dhabi, P.O. Box 15551, UAE
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Li W, Xu M, Zhang Z, Liang J, Fu R, Lin W, Luo W, Zhang X, Ren T. Regulatory Effects of 198-bp Structural Variants in the GSTA2 Promoter Region on Adipogenesis in Chickens. Int J Mol Sci 2024; 25:7155. [PMID: 39000259 PMCID: PMC11241197 DOI: 10.3390/ijms25137155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/20/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Molecular breeding accelerates animal breeding and improves efficiency by utilizing genetic mutations. Structural variations (SVs), a significant source of genetic mutations, have a greater impact on phenotypic variation than SNPs. Understanding SV functional mechanisms and obtaining precise information are crucial for molecular breeding. In this study, association analysis revealed significant correlations between 198-bp SVs in the GSTA2 promoter region and abdominal fat weight, intramuscular fat content, and subcutaneous fat thickness in chickens. High expression of GSTA2 in adipose tissue was positively correlated with the abdominal fat percentage, and different genotypes of GSTA2 exhibited varied expression patterns in the liver. The 198-bp SVs regulate GSTA2 expression by binding to different transcription factors. Overexpression of GSTA2 promoted preadipocyte proliferation and differentiation, while interference had the opposite effect. Mechanistically, the 198-bp fragment contains binding sites for transcription factors such as C/EBPα that regulate GSTA2 expression and fat synthesis. These SVs are significantly associated with chicken fat traits, positively influencing preadipocyte development by regulating cell proliferation and differentiation. Our work provides compelling evidence for the use of 198-bp SVs in the GSTA2 promoter region as molecular markers for poultry breeding and offers new insights into the pivotal role of the GSTA2 gene in fat generation.
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Affiliation(s)
- Wangyu Li
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China (R.F.); (W.L.); (W.L.)
- Guangdong Key Laboratory of Genome and Molecular Breeding of Agricultural Animals and Key Laboratory of Chicken Genetic Breeding and Reproduction, Ministry of Agriculture, Guangzhou 510642, China
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510642, China
| | - Meng Xu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Zihao Zhang
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China;
| | - Jiaying Liang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China (R.F.); (W.L.); (W.L.)
- Guangdong Key Laboratory of Genome and Molecular Breeding of Agricultural Animals and Key Laboratory of Chicken Genetic Breeding and Reproduction, Ministry of Agriculture, Guangzhou 510642, China
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510642, China
| | - Rong Fu
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China (R.F.); (W.L.); (W.L.)
- Guangdong Key Laboratory of Genome and Molecular Breeding of Agricultural Animals and Key Laboratory of Chicken Genetic Breeding and Reproduction, Ministry of Agriculture, Guangzhou 510642, China
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510642, China
| | - Wujian Lin
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China (R.F.); (W.L.); (W.L.)
- Guangdong Key Laboratory of Genome and Molecular Breeding of Agricultural Animals and Key Laboratory of Chicken Genetic Breeding and Reproduction, Ministry of Agriculture, Guangzhou 510642, China
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510642, China
| | - Wen Luo
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China (R.F.); (W.L.); (W.L.)
- Guangdong Key Laboratory of Genome and Molecular Breeding of Agricultural Animals and Key Laboratory of Chicken Genetic Breeding and Reproduction, Ministry of Agriculture, Guangzhou 510642, China
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510642, China
| | - Xiquan Zhang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China (R.F.); (W.L.); (W.L.)
- Guangdong Key Laboratory of Genome and Molecular Breeding of Agricultural Animals and Key Laboratory of Chicken Genetic Breeding and Reproduction, Ministry of Agriculture, Guangzhou 510642, China
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510642, China
| | - Tuanhui Ren
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China (R.F.); (W.L.); (W.L.)
- Guangdong Key Laboratory of Genome and Molecular Breeding of Agricultural Animals and Key Laboratory of Chicken Genetic Breeding and Reproduction, Ministry of Agriculture, Guangzhou 510642, China
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510642, China
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
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Boychenko S, Egorova VS, Brovin A, Egorov AD. White-to-Beige and Back: Adipocyte Conversion and Transcriptional Reprogramming. Pharmaceuticals (Basel) 2024; 17:790. [PMID: 38931457 PMCID: PMC11206576 DOI: 10.3390/ph17060790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/11/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution of hereditary and behavioral factors, such as nutritional inadequacy, along with the influences of environment and reduced physical activity. Two types of adipose tissue widely known are white and brown. While white adipose tissue functions predominantly as a key energy storage, brown adipose tissue has a greater mass of mitochondria and expresses the uncoupling protein 1 (UCP1) gene, which allows thermogenesis and rapid catabolism. Even though white and brown adipocytes are of different origin, activation of the brown adipocyte differentiation program in white adipose tissue cells forces them to transdifferentiate into "beige" adipocytes, characterized by thermogenesis and intensive lipolysis. Nowadays, researchers in the field of small molecule medicinal chemistry and gene therapy are making efforts to develop new drugs that effectively overcome insulin resistance and counteract obesity. Here, we discuss various aspects of white-to-beige conversion, adipose tissue catabolic re-activation, and non-shivering thermogenesis.
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Affiliation(s)
- Stanislav Boychenko
- Gene Therapy Department, Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sirius, Russia; (S.B.); (A.B.)
| | - Vera S. Egorova
- Biotechnology Department, Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sirius, Russia
| | - Andrew Brovin
- Gene Therapy Department, Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sirius, Russia; (S.B.); (A.B.)
| | - Alexander D. Egorov
- Gene Therapy Department, Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sirius, Russia; (S.B.); (A.B.)
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Youn I, Piao D, Park J, Ock SA, Han S, Han AR, Shin S, Seo EK. Anti-Obesity Activities of the Compounds from Perilla frutescens var. acuta and Chemical Profiling of the Extract. Molecules 2024; 29:2465. [PMID: 38893341 PMCID: PMC11174005 DOI: 10.3390/molecules29112465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Perilla frutescens var. acuta (Lamiaceae) is widely used not only as an oil or a spice, but also as a traditional medicine to treat colds, coughs, fever, and indigestion. As an ongoing effort, luteolin-7-O-diglucuronide (1), apigenin-7-O-diglucuronide (2), and rosmarinic acid (3) isolated from P. frutescens var. acuta were investigated for their anti-adipogenic and thermogenic activities in 3T3-L1 cells. Compound 1 exhibited a strong inhibition against adipocyte differentiation by suppressing the expression of Pparg and Cebpa over 52.0% and 45.0%, respectively. Moreover, 2 inhibited the expression of those genes in a dose-dependent manner [Pparg: 41.7% (5 µM), 62.0% (10 µM), and 81.6% (50 µM); Cebpa: 13.8% (5 µM), 18.4% (10 µM), and 37.2% (50 µM)]. On the other hand, the P. frutescens var. acuta water extract showed moderate thermogenic activities. Compounds 1 and 3 also induced thermogenesis in a dose-dependent manner by stimulating the mRNA expressions of Ucp1, Pgc1a, and Prdm16. Moreover, an LC-MS/MS chromatogram of the extract was acquired using UHPLC-MS2 and it was analyzed by feature-based molecular networking (FBMN) and the Progenesis QI software (version 3.0). The chemical profiling of the extract demonstrated that flavonoids and their glycoside derivatives, including those isolated earlier as well as rosmarinic acid, are present in P. frutescens var. acuta.
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Affiliation(s)
- Isoo Youn
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea; (I.Y.); (D.P.); (S.H.)
| | - Donglan Piao
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea; (I.Y.); (D.P.); (S.H.)
| | - Jisu Park
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea; (J.P.); (A.-R.H.)
| | - Seung A Ock
- Department of Food and Nutrition, Seoul Women’s University, Seoul 01797, Republic of Korea;
| | - Sujin Han
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea; (I.Y.); (D.P.); (S.H.)
| | - Ah-Reum Han
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea; (J.P.); (A.-R.H.)
| | - Sunhye Shin
- Department of Food and Nutrition, Seoul Women’s University, Seoul 01797, Republic of Korea;
| | - Eun Kyoung Seo
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea; (I.Y.); (D.P.); (S.H.)
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Sakaguchi K, Okiyama Y, Tanaka S. In Silico Search for Drug Candidates Targeting the PAX8-PPARγ Fusion Protein in Thyroid Cancer. Int J Mol Sci 2024; 25:5347. [PMID: 38791384 PMCID: PMC11121424 DOI: 10.3390/ijms25105347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/05/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
The PAX8/PPARγ rearrangement, producing the PAX8-PPARγ fusion protein (PPFP), is thought to play an essential role in the oncogenesis of thyroid follicular tumors. To identify PPFP-targeted drug candidates and establish an early standard of care for thyroid tumors, we performed ensemble-docking-based compound screening. Specifically, we investigated the pocket structure that should be adopted to search for a promising ligand compound for the PPFP; the position of the ligand-binding pocket on the PPARγ side of the PPFP is similar to that of PPARγ; however, the shape is slightly different between them due to environmental factors. We developed a method for selecting a PPFP structure with a relevant pocket and high prediction accuracy for ligand binding. This method was validated using PPARγ, whose structure and activity values are known for many compounds. Then, we performed docking calculations to the PPFP for 97 drug or drug-like compounds registered in the DrugBank database with a thiazolidine backbone, which is one of the characteristics of ligands that bind well to PPARγ. Furthermore, the binding affinities of promising ligand candidates were estimated more reliably using the molecular mechanics Poisson-Boltzmann surface area method. Thus, we propose promising drug candidates for the PPFP with a thiazolidine backbone.
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Affiliation(s)
| | - Yoshio Okiyama
- Graduate School of System Informatics, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan
| | - Shigenori Tanaka
- Graduate School of System Informatics, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan
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50
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Matsui T, Taniguchi S, Ishii M. Function of alveolar macrophages in lung cancer microenvironment. Inflamm Regen 2024; 44:23. [PMID: 38720352 PMCID: PMC11077793 DOI: 10.1186/s41232-024-00335-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 04/27/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Cancer tissues contain a wide variety of immune cells that play critical roles in suppressing or promoting tumor progression. Macrophages are one of the most predominant populations in the tumor microenvironment and are composed of two classes: infiltrating macrophages from the bone marrow and tissue-resident macrophages (TRMs). This review aimed to outline the function of TRMs in the tumor microenvironment, focusing on lung cancer. REVIEW Although the functions of infiltrating macrophages and tumor-associated macrophages have been intensively analyzed, a comprehensive understanding of TRM function in cancer is relatively insufficient because it differs depending on the tissue and organ. Alveolar macrophages (AMs), one of the most important TRMs in the lungs, are replenished in situ, independent of hematopoietic stem cells in the bone marrow, and are abundant in lung cancer tissue. Recently, we reported that AMs support cancer cell proliferation and contribute to unfavorable outcomes. CONCLUSION In this review, we introduce the functions of AMs in lung cancer and their underlying molecular mechanisms. A thorough understanding of the functions of AMs in lung cancer will lead to improved treatment outcomes.
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Affiliation(s)
- Takahiro Matsui
- Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
- Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
| | - Seiji Taniguchi
- Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Thoracic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Thoracic Surgery, Osaka Habikino Medical Center, Habikino, Osaka, Japan
| | - Masaru Ishii
- Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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