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Schlidt K, Asgardoon M, Febre-Alemañy DA, El-Mallah JC, Waldron O, Dawes J, Agrawal S, Landmesser ME, Ravnic DJ. Surgical Bioengineering of the Microvasculature and Challenges in Clinical Translation. TISSUE ENGINEERING. PART B, REVIEWS 2025. [PMID: 40171780 DOI: 10.1089/ten.teb.2024.0242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
Tissue and organ dysfunction are major causes of worldwide morbidity and mortality with all medical specialties being impacted. Tissue engineering is an interdisciplinary field relying on the combination of scaffolds, cells, and biologically active molecules to restore form and function. However, clinical translation is still largely hampered by limitations in vascularization. Consequently, a thorough understanding of the microvasculature is warranted. This review provides an overview of (1) angiogenesis, including sprouting angiogenesis, intussusceptive angiogenesis, vascular remodeling, vascular co-option, and inosculation; (2) strategies for vascularized engineered tissue fabrication such as scaffold modulation, prevascularization, growth factor utilization, and cell-based approaches; (3) guided microvascular development via scaffold modulation with electromechanical cues, 3D bioprinting, and electrospinning; (4) surgical approaches to bridge the micro- and macrovasculatures in order to hasten perfusion; and (5) building specific vasculature in the context of tissue repair and organ transplantation, including skin, adipose, bone, liver, kidney, and lung. Our goal is to provide the reader with a translational overview that spans developmental biology, tissue engineering, and clinical surgery.
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Affiliation(s)
- Kevin Schlidt
- Zubar Plastic Surgery Research Laboratory, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Mohamadhossein Asgardoon
- Zubar Plastic Surgery Research Laboratory, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - David A Febre-Alemañy
- Zubar Plastic Surgery Research Laboratory, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Jessica C El-Mallah
- Zubar Plastic Surgery Research Laboratory, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Olivia Waldron
- Zubar Plastic Surgery Research Laboratory, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Jazzmyn Dawes
- Zubar Plastic Surgery Research Laboratory, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Shailaja Agrawal
- Zubar Plastic Surgery Research Laboratory, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Mary E Landmesser
- Zubar Plastic Surgery Research Laboratory, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Dino J Ravnic
- Zubar Plastic Surgery Research Laboratory, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
- Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA
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Zhang L, Xia Z, Li Z, Zhang J, Wang K, Wang W. Influence of body fat tissue on outcomes in patients undergoing hepatectomy or liver transplantation: a systematic review and meta-analysis. Int J Surg 2025; 111:1167-1181. [PMID: 38920322 PMCID: PMC11745742 DOI: 10.1097/js9.0000000000001864] [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: 04/24/2024] [Accepted: 06/08/2024] [Indexed: 06/27/2024]
Abstract
OBJECTIVE The purpose of this study is to investigate potential associations between body fat composition and postoperative outcomes in patients with hepatectomy or liver transplantation. METHODS Three online databases, including Embase, PubMed, and the Cochrane Library, were thoroughly searched for literature describing the relationship between body fat composition and outcomes of patients with liver surgery from the start of each database to 29 October 2023. The Newcastle-Ottawa Scale was used to rate the quality of the studies. RESULTS This analysis included a total of 29 articles with a combined patient cohort of 6435 individuals. The results demonstrated that patients with high intramuscular fat content (IMFC) had significantly inferior overall survival (OS) [hazard ratio (HR): 2.07, 95% CI: 1.69-2.53, P <0.001] and recurrence-free survival (RFS) (HR: 1.61, 95% CI: 1.20-2.16, P =0.002) and a higher risk of major complications (HR: 2.20, 95% CI: 1.59-3.05, P <0.001). We also found that the presence of high visceral-to-subcutaneous fat tissue ratio (VSR) in patients with liver surgery was significantly related to poorer OS (HR: 1.70, 95% CI: 1.44-2.00, P <0.001) and progression-free survival (PFS) (HR: 1.29, 95% CI: 1.11-1.50, P =0.001) and a higher major complication rate (HR: 2.31, 95% CI: 1.17-4.56, P =0.016). Besides, the synthesized findings indicated there is no significant correlation between visceral fat tissue and survival outcomes or postoperative complications. CONCLUSION In summary, preoperative IMFC and VSR have the potential to forecast poorer OS and RFS and a higher risk of complications for patients undergoing hepatectomy or liver transplantation.
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Affiliation(s)
- Lilong Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
| | - Zhijia Xia
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University of Munich, Munich, Germany
| | - Zhongyi Li
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University of Munich, Munich, Germany
| | - Jing Zhang
- Division of Basic Biomedical Sciences, The University of South Dakota Sanford School of Medicine, Vermillion, South Dakota, USA
| | - Kunpeng Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
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Varalda M, Venetucci J, Nikaj H, Kankara CR, Garro G, Keivan N, Bettio V, Marzullo P, Antona A, Valente G, Gentilli S, Capello D. Second-Generation Antipsychotics Induce Metabolic Disruption in Adipose Tissue-Derived Mesenchymal Stem Cells Through an aPKC-Dependent Pathway. Cells 2024; 13:2084. [PMID: 39768174 PMCID: PMC11674800 DOI: 10.3390/cells13242084] [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: 10/04/2024] [Revised: 12/06/2024] [Accepted: 12/14/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities, including visceral obesity, dyslipidemia, and insulin resistance. In this regard, visceral white adipose tissue (vWAT) plays a critical role, influencing energy metabolism, immunomodulation, and oxidative stress. Adipose-derived stem cells (ADSCs) are key players in these processes within vWAT. While second-generation antipsychotics (SGAs) have significantly improved treatments for mental health disorders, their chronic use is associated with an increased risk of MetS. In this study, we explored the impact of SGAs on ADSCs to better understand their role in MetS and identify potential therapeutic targets. Our findings reveal that olanzapine disrupts lipid droplet formation during adipogenic differentiation, impairing insulin receptor endocytosis, turnover, and signaling. SGAs also alter the endolysosomal compartment, leading to acidic vesicle accumulation and increased lysosomal biogenesis through TFEB activation. PKCζ is crucial for the SGA-induced nuclear translocation of TFEB and acidic vesicle formation. Notably, inhibiting PKCζ restored insulin receptor tyrosine phosphorylation, normalized receptor turnover, and improved downstream signaling following olanzapine treatment. This activation of PKCζ by olanzapine is driven by increased phosphatidic acid synthesis via phospholipase D (PLD), following G protein-coupled receptor (GPCR) signaling activation. Overall, olanzapine and clozapine disrupt endolysosomal homeostasis and insulin signaling in a PKCζ-dependent manner. These findings highlight SGAs as valuable tools for uncovering cellular dysfunction in vWAT during MetS and may guide the development of new therapeutic strategies to mitigate the metabolic side effects of these drugs.
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Affiliation(s)
- Marco Varalda
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
- UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy
| | - Jacopo Venetucci
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
- UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy
| | - Herald Nikaj
- General Surgery Division, University of Piemonte Orientale, AOU Maggiore della Carità, 28100 Novara, Italy;
| | - Chaitanya Reddy Kankara
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
| | - Giulia Garro
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
- UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy
| | - Nazanin Keivan
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
| | - Valentina Bettio
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
- UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy
| | - Paolo Marzullo
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
| | - Annamaria Antona
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
| | - Guido Valente
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
- Pathology Unity, Ospedale “Sant’Andrea”, 13100 Vercelli, Italy
| | - Sergio Gentilli
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
- General Surgery Division, University of Piemonte Orientale, AOU Maggiore della Carità, 28100 Novara, Italy;
- Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy
| | - Daniela Capello
- Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
- UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy
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Hu B, Wang Z, Ma T, Fan P, Li L. Research progress on the pathogenesis of multiple symmetrical lipomatosis. Adipocyte 2024; 13:2416681. [PMID: 39648639 PMCID: PMC11487982 DOI: 10.1080/21623945.2024.2416681] [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: 02/28/2024] [Revised: 10/08/2024] [Accepted: 10/09/2024] [Indexed: 12/10/2024] Open
Abstract
Multiple symmetric lipomatosis, also known as madelung's disease, is a rare syndrome characterized by the accumulation of multiple symmetric subcutaneous adipose tissues that significantly affect patients' quality of life. Since the aetiology of the disease is still unclear, surgical intervention by doctors based on clinical experience is currently the main treatment. However, the recurrence rate remains high even after surgical intervention. Therefore, studying the pathogenesis of this disease is particularly important for overcoming this challenge. In this paper, we reviewed and summarized recent research results on the pathogenesis of this disease to provide possible research directions and treatment strategies for this disease, but no clear mechanism was identified.'Level of Evidence: Level I, Review Articles'.
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Affiliation(s)
- Bo Hu
- Department of Plastic and Cosmetic Surgery, Hosp Hainan Prov, Hainan Gen Hosp, Hainan Med Univ, Hainan Affiliated Hosp, Haikou, P. R. China
| | - Ze Wang
- Department of Plastic and Cosmetic Surgery, Hosp Hainan Prov, Hainan Gen Hosp, Hainan Med Univ, Hainan Affiliated Hosp, Haikou, P. R. China
| | - Tengxiao Ma
- Department of Plastic and Cosmetic Surgery, Hosp Hainan Prov, Hainan Gen Hosp, Hainan Med Univ, Hainan Affiliated Hosp, Haikou, P. R. China
| | - Pengfei Fan
- Department of Plastic and Cosmetic Surgery, Hosp Hainan Prov, Hainan Gen Hosp, Hainan Med Univ, Hainan Affiliated Hosp, Haikou, P. R. China
| | - Lei Li
- Department of Plastic and Cosmetic Surgery, Hosp Hainan Prov, Hainan Gen Hosp, Hainan Med Univ, Hainan Affiliated Hosp, Haikou, P. R. China
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Wang L, Sesachalam PV, Chua R, Ghosh S. In silico and functional analysis identifies key gene networks and novel gene candidates in obesity-linked human visceral fat. Obesity (Silver Spring) 2024; 32:1998-2011. [PMID: 39497634 PMCID: PMC11548800 DOI: 10.1002/oby.24161] [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: 12/22/2023] [Revised: 08/21/2024] [Accepted: 08/23/2024] [Indexed: 11/10/2024]
Abstract
OBJECTIVE Visceral adiposity is associated with increased proinflammatory activity, insulin resistance, diabetes risk, and mortality rate. Numerous individual genes have been associated with obesity, but studies investigating gene regulatory networks in human visceral obesity have been lacking. METHODS We analyzed gene regulatory networks in human visceral adipose tissue (VAT) from 48 and 11 Chinese patients with and without obesity, respectively, using gene coexpression and gene regulatory network construction from RNA-sequencing data. We also conducted RNA interference-based functional tests on selected genes for effects on adipocyte differentiation. RESULTS A scale-free gene coexpression network was constructed from 360 differentially expressed genes between VAT samples from patients with and without obesity (absolute log fold change > 1, false discovery rate [FDR] < 0.05), with edge probability > 0.8. Gene regulatory network analysis identified candidate transcription factors associated with differentially expressed genes. A total of 15 subnetworks (communities) displayed altered connectivity patterns between obesity and nonobesity networks. Genes in proinflammatory pathways showed increased network connectivity in VAT samples with obesity, whereas the oxidative phosphorylation pathway displayed reduced connectivity (enrichment FDR < 0.05). Functional screening via RNA interference identified genes such as SOX30, SIRPB1, and OSBPL3 as potential network-derived candidates influencing adipocyte differentiation. CONCLUSIONS This approach highlights the network architecture in human obesity, identifies novel candidate genes, and generates new hypotheses regarding network-assisted gene regulation in VAT.
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Affiliation(s)
- Lijin Wang
- Centre for Computational Biology, Duke-NUS Medical School, Singapore
| | | | - Ruiming Chua
- Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
- National Neurosciences Institute, Singapore
| | - Sujoy Ghosh
- Centre for Computational Biology, Duke-NUS Medical School, Singapore
- Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
- Laboratory of Bioinformatics and Computational Biology, Pennington Biomedical Research Center, Baton Rouge, LA, USA
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Gu C, Tang Q, Li L, Chen Y. Optimization and Implication of Adipose-Derived Stem Cells in Craniofacial Bone Regeneration and Repair. Bioengineering (Basel) 2024; 11:1100. [PMID: 39593759 PMCID: PMC11592193 DOI: 10.3390/bioengineering11111100] [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: 09/14/2024] [Revised: 10/17/2024] [Accepted: 10/27/2024] [Indexed: 11/28/2024] Open
Abstract
Adipose-derived stem cells (ADSCs) have emerged as a promising resource for craniofacial bone regeneration due to their high abundance and easy accessibility, significant osteogenic potential, versatile applications, and potential for personalized medicine, which underscore their importance in this field. This article reviews the current progress of preclinical studies that describe the careful selection of specific ADSC subpopulations, key signaling pathways involved, and usage of various strategies to enhance the osteogenic potential of ADSCs. Additionally, clinical case reports regarding the application of ADSCs in the repair of calvarial defects, cranio-maxillofacial defects, and alveolar bone defects are also discussed.
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Affiliation(s)
- Cong Gu
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
| | - Qinghuang Tang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY 14214, USA
| | - Liwen Li
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
- Department of Biological Sciences, University at Buffalo, Buffalo, NY 14260, USA
| | - YiPing Chen
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
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Kostecka A, Kalamon N, Skoniecka A, Koczkowska M, Skowron PM, Piotrowski A, Pikuła M. Adipose-derived mesenchymal stromal cells in clinical trials: Insights from single-cell studies. Life Sci 2024; 351:122761. [PMID: 38866216 DOI: 10.1016/j.lfs.2024.122761] [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: 04/02/2024] [Revised: 05/15/2024] [Accepted: 05/27/2024] [Indexed: 06/14/2024]
Abstract
Mesenchymal Stromal Cells (MSCs) offer tremendous potential for the treatment of various diseases and their healing properties have been explored in hundreds of clinical trials. These trails primarily focus on immunological and neurological disorders, as well as regenerative medicine. Adipose tissue is a rich source of mesenchymal stromal cells and methods to obtain and culture adipose-derived MSCs (AD-MSCs) have been well established. Promising results from pre-clinical testing of AD-MSCs activity prompted clinical trials that further led to the approval of AD-MSCs for the treatment of complex perianal fistulas in Crohn's disease and subcutaneous tissue defects. However, AD-MSC heterogeneity along with various manufacturing protocols or different strategies to boost their activity create the need for standardized quality control procedures and safety assessment of the intended cell product. High-resolution transcriptomic methods have been recently gaining attention, as they deliver insight into gene expression profiles of individual cells, helping to deconstruct cellular hierarchy and differentiation trajectories, and to understand cell-cell interactions within tissues. This article presents a comprehensive overview of completed clinical trials evaluating the safety and efficacy of AD-MSC treatment, together with current single-cell studies of human AD-MSC. Furthermore, our work emphasizes the increasing significance of single-cell research in elucidating the mechanisms of cellular action and predicting their therapeutic effects.
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Affiliation(s)
- Anna Kostecka
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Natalia Kalamon
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
| | - Aneta Skoniecka
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland.
| | - Magdalena Koczkowska
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Piotr M Skowron
- Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
| | - Arkadiusz Piotrowski
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Michał Pikuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland.
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Ferrero R, Rainer PY, Rumpler M, Russeil J, Zachara M, Pezoldt J, van Mierlo G, Gardeux V, Saelens W, Alpern D, Favre L, Vionnet N, Mantziari S, Zingg T, Pitteloud N, Suter M, Matter M, Schlaudraff KU, Canto C, Deplancke B. A human omentum-specific mesothelial-like stromal population inhibits adipogenesis through IGFBP2 secretion. Cell Metab 2024; 36:1566-1585.e9. [PMID: 38729152 DOI: 10.1016/j.cmet.2024.04.017] [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: 05/12/2023] [Revised: 12/22/2023] [Accepted: 04/19/2024] [Indexed: 05/12/2024]
Abstract
Adipose tissue plasticity is orchestrated by molecularly and functionally diverse cells within the stromal vascular fraction (SVF). Although several mouse and human adipose SVF cellular subpopulations have by now been identified, we still lack an understanding of the cellular and functional variability of adipose stem and progenitor cell (ASPC) populations across human fat depots. To address this, we performed single-cell and bulk RNA sequencing (RNA-seq) analyses of >30 SVF/Lin- samples across four human adipose depots, revealing two ubiquitous human ASPC (hASPC) subpopulations with distinct proliferative and adipogenic properties but also depot- and BMI-dependent proportions. Furthermore, we identified an omental-specific, high IGFBP2-expressing stromal population that transitions between mesothelial and mesenchymal cell states and inhibits hASPC adipogenesis through IGFBP2 secretion. Our analyses highlight the molecular and cellular uniqueness of different adipose niches, while our discovery of an anti-adipogenic IGFBP2+ omental-specific population provides a new rationale for the biomedically relevant, limited adipogenic capacity of omental hASPCs.
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Affiliation(s)
- Radiana Ferrero
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Pernille Yde Rainer
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Marie Rumpler
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Julie Russeil
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
| | - Magda Zachara
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
| | - Joern Pezoldt
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Guido van Mierlo
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Vincent Gardeux
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Wouter Saelens
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Daniel Alpern
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Lucie Favre
- Department of Endocrinology, Diabetology and Metabolism, University Hospital of Lausanne (CHUV), 1011 Lausanne, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland
| | - Nathalie Vionnet
- Department of Endocrinology, Diabetology and Metabolism, University Hospital of Lausanne (CHUV), 1011 Lausanne, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland
| | - Styliani Mantziari
- Department of Visceral Surgery, University Hospital of Lausanne (CHUV), Lausanne 1011, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland
| | - Tobias Zingg
- Department of Visceral Surgery, University Hospital of Lausanne (CHUV), Lausanne 1011, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland
| | - Nelly Pitteloud
- Department of Endocrinology, Diabetology and Metabolism, University Hospital of Lausanne (CHUV), 1011 Lausanne, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland
| | - Michel Suter
- Department of Visceral Surgery, University Hospital of Lausanne (CHUV), Lausanne 1011, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland
| | - Maurice Matter
- Department of Visceral Surgery, University Hospital of Lausanne (CHUV), Lausanne 1011, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland
| | | | - Carles Canto
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Bart Deplancke
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
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Papadopoulos KS, Piperi C, Korkolopoulou P. Clinical Applications of Adipose-Derived Stem Cell (ADSC) Exosomes in Tissue Regeneration. Int J Mol Sci 2024; 25:5916. [PMID: 38892103 PMCID: PMC11172884 DOI: 10.3390/ijms25115916] [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: 04/29/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Adipose-derived stem cells (ADSCs) are mesenchymal stem cells with a great potential for self-renewal and differentiation. Exosomes derived from ADSCs (ADSC-exos) can imitate their functions, carrying cargoes of bioactive molecules that may affect specific cellular targets and signaling processes. Recent evidence has shown that ADSC-exos can mediate tissue regeneration through the regulation of the inflammatory response, enhancement of cell proliferation, and induction of angiogenesis. At the same time, they may promote wound healing as well as the remodeling of the extracellular matrix. In combination with scaffolds, they present the future of cell-free therapies and promising adjuncts to reconstructive surgery with diverse tissue-specific functions and minimal adverse effects. In this review, we address the main characteristics and functional properties of ADSC-exos in tissue regeneration and explore their most recent clinical application in wound healing, musculoskeletal regeneration, dermatology, and plastic surgery as well as in tissue engineering.
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Affiliation(s)
- Konstantinos S. Papadopoulos
- Department of Plastic and Reconstructive Surgery, 401 General Military Hospital of Athens, 11525 Athens, Greece;
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, 11527 Athens, Greece
| | - Penelope Korkolopoulou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Zhu C, Teng L, Lai Y, Yao X, Fang Y, Wang Z, Lin S, Zhang H, Li Q, Li Y, Cai J, Zhang Y, Wu C, Huang B, Li A, Liu S, Lai Q. Adipose-derived stem cells promote glycolysis and peritoneal metastasis via TGF-β1/SMAD3/ANGPTL4 axis in colorectal cancer. Cell Mol Life Sci 2024; 81:189. [PMID: 38643448 PMCID: PMC11033247 DOI: 10.1007/s00018-024-05215-1] [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: 08/13/2023] [Revised: 02/07/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024]
Abstract
Peritoneal metastasis, the third most common metastasis in colorectal cancer (CRC), has a poor prognosis for the rapid progression and limited therapeutic strategy. However, the molecular characteristics and pathogenesis of CRC peritoneal metastasis are poorly understood. Here, we aimed to elucidate the action and mechanism of adipose-derived stem cells (ADSCs), a prominent component of the peritoneal microenvironment, in CRC peritoneal metastasis formation. Database analysis indicated that ADSCs infiltration was increased in CRC peritoneal metastases, and high expression levels of ADSCs marker genes predicted a poor prognosis. Then we investigated the effect of ADSCs on CRC cells in vitro and in vivo. The results revealed that CRC cells co-cultured with ADSCs exhibited stronger metastatic property and anoikis resistance, and ADSCs boosted the intraperitoneal seeding of CRC cells. Furthermore, RNA sequencing was carried out to identify the key target gene, angiopoietin like 4 (ANGPTL4), which was upregulated in CRC specimens, especially in peritoneal metastases. Mechanistically, TGF-β1 secreted by ADSCs activated SMAD3 in CRC cells, and chromatin immunoprecipitation assay showed that SMAD3 facilitated ANGPTL4 transcription by directly binding to ANGPTL4 promoter. The ANGPTL4 upregulation was essential for ADSCs to promote glycolysis and anoikis resistance in CRC. Importantly, simultaneously targeting TGF-β signaling and ANGPTL4 efficiently reduced intraperitoneal seeding in vivo. In conclusion, this study indicates that tumor-infiltrating ADSCs promote glycolysis and anoikis resistance in CRC cells and ultimately facilitate peritoneal metastasis via the TGF-β1/SMAD3/ANGPTL4 axis. The dual-targeting of TGF-β signaling and ANGPTL4 may be a feasible therapeutic strategy for CRC peritoneal metastasis.
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Affiliation(s)
- Chaojun Zhu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Lan Teng
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Yihong Lai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Xingxing Yao
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuxin Fang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Zihuan Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Simin Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Haonan Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Qingyuan Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Ye Li
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jianqun Cai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Yue Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Changjie Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Bing Huang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.
- Department of Gastroenterology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, Guangdong, China.
| | - Qiuhua Lai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.
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11
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Liebmann K, Castillo MA, Jergova S, Best TM, Sagen J, Kouroupis D. Modification of Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal. Cells 2024; 13:484. [PMID: 38534328 PMCID: PMC10969778 DOI: 10.3390/cells13060484] [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: 02/20/2024] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype. Herein, human IFP-MSC cultures were transduced with an adeno-associated virus (AAV) vector carrying a GFP-labelled gene for a CGRP antagonist peptide (aCGRP). The GFP positive aCGRP IFP-MSC were isolated and their sEVs' miRNA and protein cargos were assessed using multiplex methods. Our results showed that purified aCGRP IFP-MSC cultures yielded sEVs with cargo of 147 distinct MSC-related miRNAs. Reactome analysis of miRNAs detected in these sEVs revealed strong involvement in the regulation of target genes involved in pathways that control pain, inflammation and cartilage homeostasis. Protein array of the sEVs cargo demonstrated high presence of key immunomodulatory and reparative proteins. Stimulated macrophages exposed to aCGRP IFP-MSC sEVs demonstrated a switch towards an alternate M2 status. Also, stimulated cortical neurons exposed to aCGRP IFP-MSC sEVs modulate their molecular pain signaling profile. Collectively, our data suggest that yielded sEVs can putatively target CGRP in vivo, while containing potent anti-inflammatory and analgesic cargo, suggesting the promise for novel sEVs-based therapeutic approaches to diseases such as OA.
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Affiliation(s)
- Kevin Liebmann
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (S.J.); (J.S.)
| | - Mario A. Castillo
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Stanislava Jergova
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (S.J.); (J.S.)
| | - Thomas M. Best
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
| | - Jacqueline Sagen
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (S.J.); (J.S.)
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Wang W, Chen L, Zhang Y, Wang H, Dong D, Zhu J, Fu W, Liu T. Adipose-derived stem cells enriched with therapeutic mRNA TGF-β3 and IL-10 synergistically promote scar-less wound healing in preclinical models. Bioeng Transl Med 2024; 9:e10620. [PMID: 38435824 PMCID: PMC10905533 DOI: 10.1002/btm2.10620] [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: 08/27/2023] [Revised: 10/16/2023] [Accepted: 10/28/2023] [Indexed: 03/05/2024] Open
Abstract
Skin wound healing often leads to scar formation, presenting physical and psychological challenges for patients. Advancements in messenger RNA (mRNA) modifications offer a potential solution for pulsatile cytokine delivery to create a favorable wound-healing microenvironment, thereby preventing cutaneous fibrosis. This study aimed to investigate the effectiveness of human adipose-derived stem cells (hADSCs) enriched with N 1-methylpseudouridine (m1ψ) modified transforming growth factor-β3 (TGF-β3) and interleukin-10 (IL-10) mRNA in promoting scar-free healing in preclinical models. The results demonstrated that the modified mRNA (modRNA)-loaded hADSCs efficiently and temporarily secreted TGF-β3 and IL-10 proteins. In a dorsal injury model, hADSCs loaded with modRNA TGF-β3 and IL-10 exhibited multidimensional therapeutic effects, including improved collagen deposition, extracellular matrix organization, and neovascularization. In vitro experiments confirmed the ability of these cells to markedly inhibit the proliferation and migration of keloid fibroblasts, and reverse the myofibroblast phenotype. Finally, collagen degradation mediated by matrix metalloproteinase upregulation was observed in an ex vivo keloid explant culture model. In conclusion, the synergistic effects of the modRNA TGF-β3, IL-10, and hADSCs hold promise for establishing a scar-free wound-healing microenvironment, representing a robust foundation for the management of wounds in populations susceptible to scar formation.
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Affiliation(s)
- Wei Wang
- Department of Plastic and Aesthetic SurgeryHuadong Hospital, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Liang Chen
- Department of Plastic and Aesthetic SurgeryHuadong Hospital, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Yuxin Zhang
- Department of Plastic and Aesthetic SurgeryHuadong Hospital, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Heng Wang
- Department of Plastic and Aesthetic SurgeryHuadong Hospital, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Dong Dong
- Department of Plastic and Aesthetic SurgeryHuadong Hospital, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Jingjing Zhu
- Department of Plastic and Aesthetic SurgeryHuadong Hospital, Shanghai Medical College, Fudan UniversityShanghaiChina
| | - Wei Fu
- Institute of Pediatric Translational Medicine, Shanghai Institute of Pediatric Congenital Heart Disease, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
| | - Tianyi Liu
- Department of Plastic and Aesthetic SurgeryHuadong Hospital, Shanghai Medical College, Fudan UniversityShanghaiChina
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13
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Wang S, Xiao Y, An X, Luo L, Gong K, Yu D. A comprehensive review of the literature on CD10: its function, clinical application, and prospects. Front Pharmacol 2024; 15:1336310. [PMID: 38389922 PMCID: PMC10881666 DOI: 10.3389/fphar.2024.1336310] [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: 11/14/2023] [Accepted: 01/29/2024] [Indexed: 02/24/2024] Open
Abstract
CD10, a zinc-dependent metalloprotease found on the cell surface, plays a pivotal role in an array of physiological and pathological processes including cardiovascular regulation, immune function, fetal development, pain response, oncogenesis, and aging. Recognized as a biomarker for hematopoietic and tissue stem cells, CD10 has garnered attention for its prognostic potential in the progression of leukemia and various solid tumors. Recent studies underscore its regulatory significance and therapeutic promise in combating Alzheimer's disease (AD), and it is noted for its protective role in preventing heart failure (HF), obesity, and type-2 diabetes. Furthermore, CD10/substance P interaction has also been shown to contribute to the pain signaling regulation and immunomodulation in diseases such as complex regional pain syndrome (CRPS) and osteoarthritis (OA). The emergence of COVID-19 has sparked interest in CD10's involvement in the disease's pathogenesis. Given its association with multiple disease states, CD10 is a prime therapeutic target; inhibitors targeting CD10 are now being advanced as therapeutic agents. This review compiles recent and earlier literature on CD10, elucidating its physicochemical attributes, tissue-specific expression, and molecular functions. Furthermore, it details the association of CD10 with various diseases and the clinical advancements of its inhibitors, providing a comprehensive overview of its growing significance in medical research.
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Affiliation(s)
- Shudong Wang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yinghui Xiao
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xingna An
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Ling Luo
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Kejian Gong
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Dehai Yu
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
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14
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Parvanova A, Reseghetti E, Abbate M, Ruggenenti P. Mechanisms and treatment of obesity-related hypertension-Part 1: Mechanisms. Clin Kidney J 2024; 17:sfad282. [PMID: 38186879 PMCID: PMC10768772 DOI: 10.1093/ckj/sfad282] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Indexed: 01/09/2024] Open
Abstract
The prevalence of obesity has tripled over the past five decades. Obesity, especially visceral obesity, is closely related to hypertension, increasing the risk of primary (essential) hypertension by 65%-75%. Hypertension is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and its prevalence is rapidly increasing following the pandemic rise in obesity. Although the causal relationship between obesity and high blood pressure (BP) is well established, the detailed mechanisms for such association are still under research. For more than 30 years sympathetic nervous system (SNS) and kidney sodium reabsorption activation, secondary to insulin resistance and compensatory hyperinsulinemia, have been considered as primary mediators of elevated BP in obesity. However, experimental and clinical data show that severe insulin resistance and hyperinsulinemia can occur in the absence of elevated BP, challenging the causal relationship between insulin resistance and hyperinsulinemia as the key factor linking obesity to hypertension. The purpose of Part 1 of this review is to summarize the available data on recently emerging mechanisms believed to contribute to obesity-related hypertension through increased sodium reabsorption and volume expansion, such as: physical compression of the kidney by perirenal/intrarenal fat and overactivation of the systemic/renal SNS and the renin-angiotensin-aldosterone system. The role of hyperleptinemia, impaired chemoreceptor and baroreceptor reflexes, and increased perivascular fat is also discussed. Specifically targeting these mechanisms may pave the way for a new therapeutic intervention in the treatment of obesity-related hypertension in the context of 'precision medicine' principles, which will be discussed in Part 2.
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Affiliation(s)
- Aneliya Parvanova
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Elia Reseghetti
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Manuela Abbate
- Research Group on Global Health, University of the Balearic Islands, Palma, Spain
- Research Group on Global Health and Lifestyle, Health Research Institutte of the Balearic Islands (IdISBa), Palma, Spain
| | - Piero Ruggenenti
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
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Tran ANT, Kim HY, Oh SY, Kim HS. CD49f and CD146: A Possible Crosstalk Modulates Adipogenic Differentiation Potential of Mesenchymal Stem Cells. Cells 2023; 13:55. [PMID: 38201259 PMCID: PMC10778538 DOI: 10.3390/cells13010055] [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: 10/21/2023] [Revised: 12/07/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND The lack of appropriate mesenchymal stem cells (MSCs) selection methods has given the challenges for standardized harvesting, processing, and phenotyping procedures of MSCs. Genetic engineering coupled with high-throughput proteomic studies of MSC surface markers arises as a promising strategy to identify stem cell-specific markers. However, the technical limitations are the key factors making it less suitable to provide an appropriate starting material for the screening platform. A more accurate, easily accessible approach is required to solve the issues. METHODS This study established a high-throughput screening strategy with forward versus side scatter gating to identify the adipogenesis-associated markers of bone marrow-derived MSCs (BMSCs) and tonsil-derived MSCs (TMSCs). We classified the MSC-derived adipogenic differentiated cells into two clusters: lipid-rich cells as side scatter (SSC)-high population and lipid-poor cells as SSC-low population. By screening the expression of 242 cell surface proteins, we identified the surface markers which exclusively found in lipid-rich subpopulation as the specific markers for BMSCs and TMSCs. RESULTS High-throughput screening of the expression of 242 cell surface proteins indicated that CD49f and CD146 were specific for BMSCs and TMSCs. Subsequent immunostaining confirmed the consistent specific expression of CD49f and CD146 and in BMSCs and TMSCs. Enrichment of MSCs by CD49f and CD146 surface markers demonstrated that the simultaneous expression of CD49f and CD146 is required for adipogenesis and osteogenesis of mesenchymal stem cells. Furthermore, the fate decision of MSCs from different sources is regulated by distinct responses of cells to differentiation stimulations despite sharing a common CD49f+CD146+ immunophenotype. CONCLUSIONS We established an accurate, robust, transgene-free method for screening adipogenesis associated cell surface proteins. This provided a valuable tool to investigate MSC-specific markers. Additionally, we showed a possible crosstalk between CD49f and CD146 modulates the adipogenesis of MSCs.
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Affiliation(s)
- An Nguyen-Thuy Tran
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea; (A.N.-T.T.); (H.Y.K.)
- Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Ha Yeong Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea; (A.N.-T.T.); (H.Y.K.)
| | - Se-Young Oh
- Department of Convergence Medicine, Ewha Womans University Mokdong Hospital, Ewha Womans University, Seoul 07985, Republic of Korea;
| | - Han Su Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea; (A.N.-T.T.); (H.Y.K.)
- Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul 03760, Republic of Korea
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Wang L, Sesachalam PV, Chua R, Ghosh S. Interactome Analysis of Visceral Adipose Tissue Elucidates Gene Regulatory Networks and Novel Gene Candidates in Obesity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.21.572734. [PMID: 38187694 PMCID: PMC10769441 DOI: 10.1101/2023.12.21.572734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Objective Visceral adiposity is associated with increased proinflammatory activity, insulin resistance, diabetes risk and mortality rate. Numerous individual genes have been associated with obesity, but studies investigating gene-regulatory networks in human visceral obesity are lacking. Methods We analyzed gene-regulatory networks in human visceral adipose tissue (VAT) from 48 obese and 11 non-obese Chinese subjects using gene co-expression and network construction with RNA-sequencing data. We also conducted RNA interference-based tests on selected genes for adipocyte differentiation effects. Results A scale-free gene co-expression network was constructed from 360 differentially expressed genes between obese and non-obese VAT (absolute log fold-change >1, FDR<0.05) with edge probability >0.8. Gene regulatory network analysis identified candidate transcription factors associated with differentially expressed genes. Fifteen subnetworks (communities) displayed altered connectivity patterns between obese and non-obese networks. Genes in pro-inflammatory pathways showed increased network connectivities in obese VAT whereas the oxidative phosphorylation pathway displayed reduced connections (enrichment FDR<0.05). Functional screening via RNA interference identified SOX30 and OSBPL3 as potential network-derived gene candidates influencing adipocyte differentiation. Conclusions This interactome-based approach highlights the network architecture, identifies novel candidate genes, and leads to new hypotheses regarding network-assisted gene regulation in obese vs. non-obese VAT.What is already known about this subject?: Visceral adipose tissue (VAT) is associated with increased levels of proinflammatory activity, insulin resistance, diabetes risk and mortality rate.Gene expression studies have identified candidate genes associated with proinflammatory function in VAT.What are the new findings in your manuscript?: Using integrative network-science, we identified co-expression and gene regulatory networks that are differentially regulated in VAT samples from subjects with and without obesityWe used functional testing (adipocyte differentiation) to validate a subset of novel candidate genes with minimal prior reported associations to obesityHow might your results change the direction of research or the focus of clinical practice: Network biology-based investigation provides a new avenue to our understanding of gene function in visceral adiposityFunctional validation screen allows for the identification of novel gene candidates that may be targeted for the treatment of adipose tissue dysfunction in obesity.
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Chua R, Ghosh S. An optimized method for gene knockdown in differentiating human and mouse adipocyte cultures. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.14.571780. [PMID: 38168248 PMCID: PMC10760114 DOI: 10.1101/2023.12.14.571780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Adipocyte cultures are a mainstay of metabolic disease research, yet loss-of-function studies in differentiating adipocytes is complicated by the refractoriness of lipid-containing adipocytes to standard siRNA transfections. Alternative methods, such as electroporation or adenovirus/lentivirus-based delivery systems are complex, expensive and often accompanied with unacceptable levels of cell death. To address this problem, we have tested two commercially available siRNA delivery systems in this study using a multi-parameter optimization approach. Our results identified a uniform siRNA transfection protocol that can be applied to human and mouse adipocyte cultures throughout the time course of differentiation, beginning with pre-differentiated cells and continuing up to lipid-accumulated differentiated adipocytes. Our findings allow for efficient transfection of human and mouse adipocyte cultures using standard and readily available methodologies, and should help significantly expand the scope of gene manipulation studies in these cell types.
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Affiliation(s)
- Ruiming Chua
- Program in Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore
| | - Sujoy Ghosh
- Program in Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore
- Laboratory of Computational Biology, Pennington Biomedical Research Center, LA, USA
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18
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Chaikijurajai T, Rincon-Choles H, Tang WHW. Natriuretic peptide testing strategies in heart failure: A 2023 update. Adv Clin Chem 2023; 118:155-203. [PMID: 38280805 DOI: 10.1016/bs.acc.2023.11.005] [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] [Indexed: 01/29/2024]
Abstract
Natriuretic peptides (NPs), including B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), have been recommended as standard biomarkers for diagnosing heart failure (HF), and one of the strongest risk predictors for mortality and HF hospitalization regardless of ejection fraction (EF) and etiology of HF. BNP is an active neurohormone opposing renin-angiotensin-aldosterone and sympathetic nervous system overactivated in HF, whereas NT-proBNP is an inactive prohormone released from cardiomyocytes in response to wall stress. Despite substantial advances in the development of guideline-directed medical therapy (GDMT) for HF with reduced EF, studies demonstrating direct benefits of NP-guided chronic HF therapy on mortality, HF hospitalization, and GDMT optimization have yielded conflicting results. However, accumulating evidence shows that achieving prespecified BNP or NT-proBNP target over time is significantly associated with favorable outcomes, suggesting that benefits of serially measured NPs may be limited to particular groups of HF patients, such as those with extreme levels of baseline BNP or NT-proBNP, which could represent severe phenotypes of HF associated with natriuretic peptide resistance or cardiorenal syndrome. Over the past decade, clinical utilization of BNP and NT-proBNP has been expanded, especially using serial NP measurements for guiding HF therapy, optimizing GDMT and identifying at-risk patients with HF phenotypes who may be minimally symptomatic or asymptomatic.
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Affiliation(s)
- Thanat Chaikijurajai
- Kaufman Center for Heart Failure Treatment and Recovery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, United States; Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Hernan Rincon-Choles
- Department of Nephrology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, United States
| | - W H Wilson Tang
- Kaufman Center for Heart Failure Treatment and Recovery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, United States.
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19
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Smolinska A, Bzinkowska A, Rybkowska P, Chodkowska M, Sarnowska A. Promising Markers in the Context of Mesenchymal Stem/Stromal Cells Subpopulations with Unique Properties. Stem Cells Int 2023; 2023:1842958. [PMID: 37771549 PMCID: PMC10533301 DOI: 10.1155/2023/1842958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/11/2023] [Accepted: 08/25/2023] [Indexed: 09/30/2023] Open
Abstract
The heterogeneity of the mesenchymal stem/stromal cells (MSCs) population poses a challenge to researchers and clinicians, especially those observed at the population level. What is more, the lack of precise evidences regarding MSCs developmental origin even further complicate this issue. As the available evidences indicate several possible pathways of MSCs formation, this diverse origin may be reflected in the unique subsets of cells found within the MSCs population. Such populations differ in specialization degree, proliferation, and immunomodulatory properties or exhibit other additional properties such as increased angiogenesis capacity. In this review article, we attempted to identify such outstanding populations according to the specific surface antigens or intracellular markers. Described groups were characterized depending on their specialization and potential therapeutic application. The reports presented here cover a wide variety of properties found in the recent literature, which is quite scarce for many candidates mentioned in this article. Even though the collected information would allow for better targeting of specific subpopulations in regenerative medicine to increase the effectiveness of MSC-based therapies.
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Affiliation(s)
- Agnieszka Smolinska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Aleksandra Bzinkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Paulina Rybkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Magdalena Chodkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Anna Sarnowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
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20
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Mikłosz A, Łukaszuk B, Supruniuk E, Grubczak K, Kusaczuk M, Chabowski A. RabGAP AS160/TBC1D4 deficiency increases long-chain fatty acid transport but has little additional effect on obesity and metabolic syndrome in ADMSCs-derived adipocytes of morbidly obese women. Front Mol Biosci 2023; 10:1232159. [PMID: 37602323 PMCID: PMC10435366 DOI: 10.3389/fmolb.2023.1232159] [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: 05/31/2023] [Accepted: 07/12/2023] [Indexed: 08/22/2023] Open
Abstract
The Akt substrate of 160 kDa (AS160), also known as TBC1 domain family member 4 (TBC1D4), represents a crucial regulator of insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. Recent evidence suggests that AS160/TBC1D4 may also control the cellular entry of long-chain fatty acids (LCFAs), resulting in changes to the lipid profile of muscles and fat cells in lean subjects. However, there are virtually no data on AS160/TBC1D4 expression and its modulatory role in lipid metabolism in the adipocytes from morbidly obese individuals of different metabolic status. In this study, we evaluated the effect of the three main factors, i.e., AS160 silencing, obesity, and metabolic syndrome on lipid uptake and profile in fully differentiated adipocytes derived from mesenchymal stem cells (ADMSCs) of lean and obese (with/without metabolic syndrome) postmenopausal women. Additionally, we tested possible interactions between the explanatory variables. In general, obesity translated into a greater content of fatty acid transporters (especially CD36/SR-B2 and SLC27A4/FATP4) and boosted accumulation of all the examined lipid fractions, i.e., triacylglycerols (TAGs), diacylglycerols (DAGs), and free fatty acids (FFAs). The aforementioned were further enhanced by metabolic syndrome. Moreover, AS160 deficiency also increased the abundance of SLC27A4/FATP4 and CD36/SR-B2, especially on the cell surface of the adipocytes derived from ADMSCs of subcutaneous deposit. This was further accompanied by increased LCFA (palmitic acid) uptake. Despite the aforementioned, AS160 silencing seemed unable to significantly affect the phenotype of the adipocytes stemming from obese patients with respect to their cellular lipid profile as we observed virtually no changes in TAG, DAG, and FFA contents when compared to cells with the reference level of proteins. Nevertheless, knockdown of AS160 stimulated fatty acid oxidation, which may indicate that adaptive mechanisms counteract excessive lipid accumulation. At the same time, adipocytes of visceral origin were rather insensitive to the applied intervention.
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Affiliation(s)
- Agnieszka Mikłosz
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Bartłomiej Łukaszuk
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Elżbieta Supruniuk
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Kamil Grubczak
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland
| | - Magdalena Kusaczuk
- Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
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21
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Kouroupis D, Kaplan LD, Huard J, Best TM. CD10-Bound Human Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions. Cells 2023; 12:1824. [PMID: 37508489 PMCID: PMC10377825 DOI: 10.3390/cells12141824] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/23/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023] Open
Abstract
The onset and progression of human inflammatory joint diseases are strongly associated with the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived mesenchymal stem/stromal cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic effects are largely exerted via their CD10-bound small extracellular vesicles (IFP-MSC sEVs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation. Herein, IFP-MSC sEVs were isolated from CD10High- and CD10Low-expressing IFP-MSC cultures and their sEV miRNA cargo was assessed using multiplex methods. Functionally, we interrogated the effect of CD10High and CD10Low sEVs on stimulated by inflammatory/fibrotic cues synoviocyte monocultures and cocultures with IFP-MSC-derived chondropellets. Finally, CD10High sEVs were tested in vivo for their therapeutic capacity in an animal model of acute synovitis/fat pad fibrosis. Our results showed that CD10High and CD10Low sEVs possess distinct miRNA profiles. Reactome analysis of miRNAs highly present in sEVs showed their involvement in the regulation of six gene groups, particularly those involving the immune system. Stimulated synoviocytes exposed to IFP-MSC sEVs demonstrated significantly reduced proliferation and altered inflammation-related molecular profiles compared to control stimulated synoviocytes. Importantly, CD10High sEV treatment of stimulated chondropellets/synoviocyte cocultures indicated significant chondroprotective effects. Therapeutically, CD10High sEV treatment resulted in robust chondroprotective effects by retaining articular cartilage structure/composition and PRG4 (lubricin)-expressing cartilage cells in the animal model of acute synovitis/IFP fibrosis. Our study suggests that CD10High sEVs possess immunomodulatory miRNA attributes with strong chondroprotective/anabolic effects for articular cartilage in vivo. The results could serve as a foundation for sEV-based therapeutics for the resolution of detrimental aspects of immune-mediated inflammatory joint changes associated with conditions such as osteoarthritis (OA).
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Affiliation(s)
- Dimitrios Kouroupis
- Department of Orthopaedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Lee D. Kaplan
- Department of Orthopaedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA (T.M.B.)
| | - Johnny Huard
- Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA;
| | - Thomas M. Best
- Department of Orthopaedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA (T.M.B.)
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22
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Wei F, Tuong ZK, Omer M, Ngo C, Asiatico J, Kinzel M, Pugazhendhi AS, Khaled AR, Ghosh R, Coathup M. A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss. Bone Res 2023; 11:34. [PMID: 37385982 DOI: 10.1038/s41413-023-00273-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 05/16/2023] [Accepted: 05/28/2023] [Indexed: 07/01/2023] Open
Abstract
Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone. Presently, no effective countermeasure exists, and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity. The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy. Our studies revealed that P7C3 repressed ionizing radiation (IR)-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition in vitro. We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened, osteoporotic bone. However, the administration of P7C3 significantly inhibited osteoclastic activity, lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area, architecture, and mechanical strength. Our findings revealed significant enhancement of cellular macromolecule metabolic processes, myeloid cell differentiation, and the proteins LRP-4, TAGLN, ILK, and Tollip, with downregulation of GDF-3, SH2B1, and CD200. These proteins are key in favoring osteoblast over adipogenic progenitor differentiation, cell matrix interactions, and shape and motility, facilitating inflammatory resolution, and suppressing osteoclastogenesis, potentially via Wnt/β-catenin signaling. A concern was whether P7C3 afforded similar protection to cancer cells. Preliminarily, and remarkably, at the same protective P7C3 dose, a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro. Together, these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy, leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications. Our data uncover a new approach for the prevention of radiation-induced bone damage, and further work is needed to investigate its ability to selectively drive cancer cell death.
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Affiliation(s)
- Fei Wei
- Biionix Cluster, and Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Zewen Kelvin Tuong
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
- Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK
| | - Mahmoud Omer
- Biionix Cluster, and Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Christopher Ngo
- Biionix Cluster, and Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Jackson Asiatico
- Department of Mechanical and Aerospace Engineering, University of Central Florida, Orlando, FL, USA
| | - Michael Kinzel
- Department of Mechanical and Aerospace Engineering, University of Central Florida, Orlando, FL, USA
| | - Abinaya Sindu Pugazhendhi
- Biionix Cluster, and Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Annette R Khaled
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Ranajay Ghosh
- Department of Mechanical and Aerospace Engineering, University of Central Florida, Orlando, FL, USA
| | - Melanie Coathup
- Biionix Cluster, and Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, USA.
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23
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Garritson JD, Zhang J, Achenbach A, Ferhat M, Eich E, Stubben CJ, Martinez PL, Ibele AR, Hilgendorf KI, Boudina S. BMPER is a marker of adipose progenitors and adipocytes and a positive modulator of adipogenesis. Commun Biol 2023; 6:638. [PMID: 37311809 PMCID: PMC10264349 DOI: 10.1038/s42003-023-05011-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 06/02/2023] [Indexed: 06/15/2023] Open
Abstract
Autocrine and paracrine signaling regulating adipogenesis in white adipose tissue remains largely unclear. Here we used single-cell RNA-sequencing (RNA-seq) and single nuclei RNA-sequencing (snRNA-seq) to identify markers of adipose progenitor cells (APCs) and adipogenic modulators in visceral adipose tissue (VAT) of humans and mice. Our study confirmed the presence of major cellular clusters in humans and mice and established important sex and diet-specific dissimilarities in cell proportions. Here we show that bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) is a conserved marker for APCs and adipocytes in VAT in humans and mice. Further, BMPER is highly enriched in lineage negative stromal vascular cells and its expression is significantly higher in visceral compared to subcutaneous APCs in mice. BMPER expression and release peaked by day four post-differentiation in 3T3-L1 preadipocytes. We reveal that BMPER is required for adipogenesis both in 3T3-L1 preadipocytes and in mouse APCs. Together, this study identified BMPER as a positive modulator of adipogenesis.
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Affiliation(s)
- Jacob D Garritson
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, 84112, USA
| | - Jiabi Zhang
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, 84112, USA
| | - Alan Achenbach
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, 84112, USA
| | - Maroua Ferhat
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, 84112, USA
| | - Emile Eich
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, 84112, USA
| | - Chris J Stubben
- Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Paige L Martinez
- Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Anna R Ibele
- Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Keren I Hilgendorf
- Department of Biochemistry, University of Utah, Salt Lake City, UT, 84112, USA
| | - Sihem Boudina
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, 84112, USA.
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24
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Petrova V, Vachkova E. Outlook of Adipose-Derived Stem Cells: Challenges to Their Clinical Application in Horses. Vet Sci 2023; 10:vetsci10050348. [PMID: 37235430 DOI: 10.3390/vetsci10050348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/05/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Adipose tissue is recognized as the major endocrine organ, potentially acting as a source of mesenchymal stem cells for various applications in regenerative medicine. Athletic horses are often exposed to traumatic injuries, resulting in severe financial losses. The development of adipose-derived stem cells' regenerative potential depends on many factors. The extraction of stem cells from subcutaneous adipose tissue is non-invasive, non-traumatic, cheaper, and safer than other sources. Since there is a lack of unique standards for identification, the isolated cells and applied differentiation protocols are often not species-specific; therefore, the cells cannot reveal their multipotent properties, so their stemness features remain questionable. The current review discusses some aspects of the specificity of equine adipose stem cells concerning their features, immunophenotyping, secretome profile, differentiation abilities, culturing conditions, and consequent possibilities for clinical application in concrete disorders. The presented new approaches elucidate the possibility of the transition from cell-based to cell-free therapy with regenerative purposes in horses as an alternative treatment to cellular therapy. In conclusion, their clinical benefits should not be underestimated due to the higher yield and the physiological properties of adipose-derived stem cells that facilitate the healing and tissue regeneration process and the ability to amplify the effects of traditional treatments. More profound studies are necessary to apply these innovative approaches when treating traumatic disorders in racing horses.
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Affiliation(s)
- Valeria Petrova
- Department of Pharmacology, Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria
| | - Ekaterina Vachkova
- Department of Pharmacology, Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria
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25
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Singh J, Singh S. Review on kidney diseases: types, treatment and potential of stem cell therapy. RENAL REPLACEMENT THERAPY 2023; 9:21. [PMID: 37131920 PMCID: PMC10134709 DOI: 10.1186/s41100-023-00475-2] [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: 04/02/2022] [Accepted: 04/11/2023] [Indexed: 05/04/2023] Open
Abstract
Renal disorders are an emerging global public health issue with a higher growth rate despite progress in supportive therapies. In order to find more promising treatments to stimulate renal repair, stem cell-based technology has been proposed as a potentially therapeutic option. The self-renewal and proliferative nature of stem cells raised the hope to fight against various diseases. Similarly, it opens a new path for the treatment and repair of damaged renal cells. This review focuses on the types of renal diseases; acute and chronic kidney disease-their statistical data, and the conventional drugs used for treatment. It includes the possible stem cell therapy mechanisms involved and outcomes recorded so far, the limitations of using these regenerative medicines, and the progressive improvement in stem cell therapy by adopting approaches like PiggyBac, Sleeping Beauty, and the Sendai virus. Specifically, about the paracrine activities of amniotic fluid stem cells, renal stem cells, embryonic stem cells, mesenchymal stem cell, induced pluripotent stem cells as well as other stem cells.
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Affiliation(s)
- Jaspreet Singh
- School of Bioengineering & Biosciences, Lovely Professional University, 15935, Block 56, Room No 202, Phagwara, Punjab 144411 India
| | - Sanjeev Singh
- School of Bioengineering & Biosciences, Lovely Professional University, 15935, Block 56, Room No 202, Phagwara, Punjab 144411 India
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26
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A Wrong Fate Decision in Adipose Stem Cells upon Obesity. Cells 2023; 12:cells12040662. [PMID: 36831329 PMCID: PMC9954614 DOI: 10.3390/cells12040662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/16/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Progress has been made in identifying stem cell aging as a pathological manifestation of a variety of diseases, including obesity. Adipose stem cells (ASCs) play a core role in adipocyte turnover, which maintains tissue homeostasis. Given aberrant lineage determination as a feature of stem cell aging, failure in adipogenesis is a culprit of adipose hypertrophy, resulting in adiposopathy and related complications. In this review, we elucidate how ASC fails in entering adipogenic lineage, with a specific focus on extracellular signaling pathways, epigenetic drift, metabolic reprogramming, and mechanical stretch. Nonetheless, such detrimental alternations can be reversed by guiding ASCs towards adipogenesis. Considering the pathological role of ASC aging in obesity, targeting adipogenesis as an anti-obesity treatment will be a key area of future research, and a strategy to rejuvenate tissue stem cell will be capable of alleviating metabolic syndrome.
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27
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Cicione C, Vadalà G, Di Giacomo G, Tilotta V, Ambrosio L, Russo F, Zampogna B, Cannata F, Papalia R, Denaro V. Micro-fragmented and nanofat adipose tissue derivatives: In vitro qualitative and quantitative analysis. Front Bioeng Biotechnol 2023; 11:911600. [PMID: 36733959 PMCID: PMC9887143 DOI: 10.3389/fbioe.2023.911600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 01/06/2023] [Indexed: 01/18/2023] Open
Abstract
Introduction: Adipose tissue is widely exploited in regenerative medicine thanks to its trophic properties, mainly based on the presence of adipose-derived stromal cells. Numerous devices have been developed to promote its clinical use, leading to the introduction of one-step surgical procedures to obtain minimally manipulated adipose tissue derivatives. However, only a few studies compared their biological properties. This study aimed to characterize micro-fragmented (MAT) and nanofat adipose tissue (NAT) obtained with two different techniques. Methods: MAT, NAT and unprocessed lipoaspirate were collected from surgical specimens. RNA extraction and collagenase isolation of stromal vascular fraction (SVF) were performed. Tissue sections were analysed by histological and immunohistochemical (collagen type I, CD31, CD34 and PCNA) staining to assess tissue morphology and cell content. qPCR was performed to evaluate the expression of stemness-related (SOX2, NANOG and OCT3/4), extracellular matrix (COL1A1) and inflammatory genes (IL1β, IL6 and iNOS). Furthermore, multilineage differentiation was assessed following culture in adipogenic and osteogenic media and staining with Oil Red O and Alizarin red. ASC immunophenotype was assessed by flow cytometric analysis of CD90, CD105, CD73 and CD45. Results: Histological and immunohistochemical results showed an increased amount of stroma and a reduction of adipocytes in MAT and NAT, with the latter displaying the highest content of collagen type I, CD31, CD34 and PCNA. From LA to MAT and NAT, an increasing expression of NANOG, SOX2, OCT3/4, COL1A1 and IL6 was noted, while no significant differences in terms of IL1β and iNOS emerged. No statistically significant differences were noted between NAT and SVF in terms of stemness-related genes, while the latter demonstrated a significantly higher expression of stress-related markers. SVF cells derived from all three samples (LA, MAT, and NAT) showed a similar ASC immunoprofile as well as osteogenic and adipogenic differentiation. Discussion: Our results showed that both MAT and NAT techniques allowed the rapid isolation of ASC-rich grafts with a high anabolic and proliferative potential. However, NAT showed the highest levels of extracellular matrix content, replicating cells, and stemness gene expression. These results may provide precious clues for the use of adipose tissue derivatives in the clinical setting.
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Affiliation(s)
- Claudia Cicione
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Gianluca Vadalà
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy,*Correspondence: Gianluca Vadalà,
| | - Giuseppina Di Giacomo
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Veronica Tilotta
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Luca Ambrosio
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Fabrizio Russo
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Biagio Zampogna
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Francesca Cannata
- Operative Research Unit of Endocrinology and Diabetes, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Rocco Papalia
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Vincenzo Denaro
- Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
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28
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Yang CH, Lin DY, Lin YS, Hsu CY, Tung MC, Tan KT, Ou YC. The Immunological Microenvironment and the Emerging Role of Stem Cells Therapy in Peyronie's Disease: A Systematic Narrative Review. Int J Mol Sci 2023; 24:ijms24010777. [PMID: 36614220 PMCID: PMC9821411 DOI: 10.3390/ijms24010777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/25/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023] Open
Abstract
Current literature has indicated that Peyronie's disease (PD) could be initiated by microtrauma and the subsequent inflammation episodes that follow. PD could be sorted into acute or chronic status, and it can differ when selecting the clinical therapeutics. PD would cause pain and penile deformity to diseased men and impair their erectile function. Occasionally, surgical revision of the penis might be needed to correct the penile curvature. We find that there are limited effective options of intra-lesion injections for the PD plaques. By searching the databases and screening the literature with the PRISMA 2020 guideline, we observed that several preclinical studies that applied stem cell therapy in treating PD were fruitful in the acute phase. Although in the chronic phase of PD, erectile parameters were not significantly improved, and therefore, future studies might be better elevated in certain aspects, such as the sites selected for harvesting stem cells or changing the centrifugation forces. In this review, we concluded the contemporary understanding of inflammatory microenvironments in PD, the stem cell therapy in PD, and our perspectives on future studies. We concluded that there may be great potential in stem cell therapy for treating both acute and chronic phases PD.
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Affiliation(s)
- Che-Hsueh Yang
- Division of Urology, Department of Surgery, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan
| | - Dian-Yu Lin
- Division of Urology, Department of Surgery, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan
- Joshua Taipei Hernia Center, Central Clinic & Hospital, Taipei 106, Taiwan
- Department of Urology, College of Medicine and Shu-Tien Urological Research Center, National Yang Ming Chiao Tung University, Taipei 106, Taiwan
| | - Yi-Sheng Lin
- Division of Urology, Department of Surgery, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan
| | - Chao-Yu Hsu
- Division of Urology, Department of Surgery, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan
| | - Min-Che Tung
- Division of Urology, Department of Surgery, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan
| | - Kok-Tong Tan
- Division of General Surgery, Department of Surgery, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan
- Correspondence: (K.-T.T.); (Y.-C.O.)
| | - Yen-Chuan Ou
- Division of Urology, Department of Surgery, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan
- Correspondence: (K.-T.T.); (Y.-C.O.)
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Autologous adipose-derived stromal vascular fraction and platelet concentrates for the treatment of complex perianal fistulas. Tech Coloproctol 2023; 27:135-143. [PMID: 36063257 PMCID: PMC9839808 DOI: 10.1007/s10151-022-02675-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 07/27/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND Complex perianal fistulas are a major challenge for modern surgery since 10-35% of patients have functional problems after treatment. Sphincter-saving techniques have a wide range of efficacy (10-80%). We hypothesised that autologous adipose-derived stromal vascular fraction in combination with platelet rich plasma is a new therapeutic strategy with enhanced cure and function preservation rates. METHODS Adult patients with complex cryptoglandular perianal fistulas were treated with injection of autologous adipose-derived stromal vascular fraction in combination with platelet rich plasma around and inside the fistulous tract between May 2018 and April 2019 at the General and Emergency Surgery Operative Unit of the University Hospital "P. Giaccone" of Palermo. Fistulas were confirmed by magnetic resonance imaging. Patients completed the Short Form-36 score on quality of life and the Wexner and Vaizey scores on faecal incontinence, and they were functionally studied using a three-dimensional anorectal manometry. The clinical and functional follow-up was performed at 1 year and 2 years after surgery. RESULTS Nine patients (4 males, 5 females; median age 42 years [19-63 years]) with high trans-sphincteric or horseshoe fistulas were treated. The average number of previous surgeries per patient was 4.8. At 1 year follow-up, 77.7% of patients were cured, while at 2 years there was 1case of relapse. The variation in Short Form-36 score in cured patients was not significant (p = 0.0936). No statistically significant differences were found in continence scores. CONCLUSIONS The proposed treatment is a treatment option that preserves sphincter integrity and function, potentially avoiding postoperative incontinence and the need of repeated treatments.
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Shahbodi M, Emami SA, Javadi B, Tayarani-Najaran Z. Effects of Thymoquinone on Adipocyte Differentiation in Human Adipose-Derived Stem Cells. Cell Biochem Biophys 2022; 80:771-779. [PMID: 36074244 DOI: 10.1007/s12013-022-01095-z] [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: 05/17/2022] [Accepted: 08/28/2022] [Indexed: 11/03/2022]
Abstract
Inhibition of adipocyte differentiation would be a key strategy to control obesity. Human adipose tissue-derived stem cells (ADSCs) are a promising tool for adipocyte differentiation research. Thymoquinone (TQ) as a potent antioxidant molecule may inhibit adipocyte differentiation. Herein, we aim to investigate the inhibitory effect of TQ on lipid differentiation in ADSCs. Quantification of cell surface markers was used by Flow-Cytometry and the effect of TQ on cell viability was assessed using the AlamarBlue test. ADSCs were subjected to induction of differentiation in the presence of non-cytotoxic concentrations of TQ (6.25, 12.5 and 25 μg/mL). Lipid accumulation was assessed using the Oil-Red O staining technique. Moreover, the expression of PPARγ (Peroxisome proliferator-activated receptor-γ) and FAS (Fatty Acid Synthetase) proteins was evaluated using Western blotting. Flow-cytometry demonstrated the expression of CD44, CD90, and CD73 as mesenchymal stem cell markers on the cell surface. At concentrations ≤100 μg/mL of TQ, no significant difference in cell viability was observed compared to the control. Lipid accumulation in ADSCs significantly decreased at 25 μg/mL (P < 0.001) and 12.5 μg/mL (P < 0.01) of TQ. The findings of the qualitative examination of Lipid Droplets also confirmed these results. Western-blot showed that TQ at 12.5 (p < 0.05) and 25 μg/mL (p < 0.01) reduced FAS/β-actin ratio compared to the positive group. TQ also decreased the expression of PPARγ at 6.25 μg/mL but not at higher concentrations. In conclusion, TQ may reduce differentiation of fat stem cells into fat cells through inhibition of the expression of PPARγ and FAS proteins and might be a potential anti-obesity compound.
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Affiliation(s)
- Monireh Shahbodi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Ahmad Emami
- Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Azadi Square, Pardis University Campus, P.O. Box: 9188617871, Mashhad, Iran
| | - Behjat Javadi
- Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Azadi Square, Pardis University Campus, P.O. Box: 9188617871, Mashhad, Iran.
| | - Zahra Tayarani-Najaran
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. .,Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Lacaze L, Bergeat D, Rousseau C, Sulpice L, Val-Laillet D, Thibault R, Boudjema K. High Visceral Fat is Associated with a Worse Survival after Liver Resection for Intrahepatic Cholangiocarcinoma. Nutr Cancer 2022; 75:339-348. [PMID: 36052974 DOI: 10.1080/01635581.2022.2117387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The impact of body composition (BC) on the prognosis of resected intrahepatic cholangiocarcinoma (ICC) has been poorly studied. Aims: i) to evaluate the prevalence of low muscle mass (MM) in patients; ii) to assess the impact of BC on patient overall survival (OS) and disease-free survival (DFS), and iii) on the incidence of postoperative complications. All consecutive patients who underwent liver resection for ICC between 2004 and 2016 and who had preoperative CT scans were included. Ninety-three patients were included. Sixty percent (55/91) had low total MM. On multivariable analysis, high visceral fat (HR 2.48, CI95% [1.63; 3.77], p < 0.0001), nodules >1 (HR 3.15 [1.67; 5.93], p = 0.0004), involvement adjacent organ (HR 6.67 [1.88; 23.69], p = 0.003), and postoperative sepsis (HR 3.04 [1.54; 5.99], p = 0.0013) were independently associated with OS. High visceral fat (HR 2.10 [1.31; 3.38], p = 0.002], nodules >1 (HR 3.01, [1.49; 6.10], p = 0.002), postoperative sepsis (HR 5.16 [2.24; 11.89], p = 0.0001), ASA score (p = 0.02) and perineural invasion (HR 3.30 [1.62; 6.76], p = 0.001) were independently associated with lower DFS. Conclusion: 60% of ICC patients had low MM before surgery. High visceral fat, but not muscle mass, was an independent prognostic factor for poor OS and DFS in European patients with resected ICC.
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Affiliation(s)
- Laurence Lacaze
- Service de Chirurgie Hépatobiliaire et Digestive, CHU Rennes, Univ Rennes, Rennes, France.,Unité de Nutrition, service Endocrinologie-Diabétologie-Nutrition, CHU Rennes, Rennes, France
| | - Damien Bergeat
- Service de Chirurgie Hépatobiliaire et Digestive, CHU Rennes, Univ Rennes, Rennes, France.,Nutrition Metabolisms and Cancer, NuMeCan, INRAE, INSERM, Univ Rennes, Rennes, France
| | - Chloé Rousseau
- INSERM-CIC 1414, Univ Rennes, Rennes, France.,Unité de biostatistiques, Univ Rennes, Rennes, France
| | - Laurent Sulpice
- Service de Chirurgie Hépatobiliaire et Digestive, CHU Rennes, Univ Rennes, Rennes, France.,Nutrition Metabolisms and Cancer, NuMeCan, INRAE, INSERM, Univ Rennes, Rennes, France.,INSERM-CIC 1414, Univ Rennes, Rennes, France
| | - David Val-Laillet
- Nutrition Metabolisms and Cancer, NuMeCan, INRAE, INSERM, Univ Rennes, Rennes, France
| | - Ronan Thibault
- Unité de Nutrition, service Endocrinologie-Diabétologie-Nutrition, CHU Rennes, Rennes, France.,Nutrition Metabolisms and Cancer, NuMeCan, INRAE, INSERM, Univ Rennes, Rennes, France
| | - Karim Boudjema
- Service de Chirurgie Hépatobiliaire et Digestive, CHU Rennes, Univ Rennes, Rennes, France.,Nutrition Metabolisms and Cancer, NuMeCan, INRAE, INSERM, Univ Rennes, Rennes, France.,INSERM-CIC 1414, Univ Rennes, Rennes, France
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Jafari F, Emami SA, Javadi B, Salmasi Z, Tayarani-Najjaran M, Tayarani-Najaran Z. Inhibitory effect of saffron, crocin, crocetin, and safranal against adipocyte differentiation in human adipose-derived stem cells. JOURNAL OF ETHNOPHARMACOLOGY 2022; 294:115340. [PMID: 35551973 DOI: 10.1016/j.jep.2022.115340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/20/2022] [Accepted: 04/30/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Saffron (Crocus sativus L.) has been introduced as a potential promising natural antioxidant with anti-obesity properties. In Persian Medicine, saffron has been used to control appetite and obesity. AIM OF THE STUDY The present study aims to investigate the effect of saffron and its bioactive compounds on adipocyte differentiation in human adipose-derived stem cells (ADSCs). MATERIALS AND METHODS Flow-Cytometric analysis was performed to quantify the cell surface markers. The extracts cytotoxicity on hASCs was measured using alamarBlue® assay whereas their activities against adipocyte differentiation were studied using Oil Red O staining. The level of Peroxisome proliferator-activated receptor-γ (PPARγ), Fatty Acid Synthetase (FAS), and Glyceraldehyde-3-phosphate dehydrogenase (GAPHD) which are key proteins in cell differentiation was investigated by western blot analysis. RESULTS Flow-cytometry revealed the mesenchymal stem cells markers, CD44 and CD90, on ADSCs surface. The saffron, crocin, and crocetin significantly inhibited adipocyte differentiation while saffron up to 20 μg/mL and crocin, crocetin and safranal up to 20 μM did not exhibit cytotoxicity. The western blotting analysis revealed a remarkable reduction in the level of PPARγ, GAPDH, and FAS proteins by 10 and 20 μM of crocin and 2.5 and 5 μM of crocetin. CONCLUSION It seems that saffron, crocin, and crocetin could efficiently inhibit the differentiation of hASCs with benefits for the treatment and prevention of obesity.
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Affiliation(s)
- Fatemeh Jafari
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Seyed Ahmad Emami
- Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Behjat Javadi
- Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Zahra Salmasi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | | | - Zahra Tayarani-Najaran
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Martinez-Garcia FD, van Dongen JA, Burgess JK, Harmsen MC. Matrix Metalloproteases from Adipose Tissue-Derived Stromal Cells Are Spatiotemporally Regulated by Hydrogel Mechanics in a 3D Microenvironment. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 9:bioengineering9080340. [PMID: 35892753 PMCID: PMC9332414 DOI: 10.3390/bioengineering9080340] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/11/2022] [Accepted: 07/16/2022] [Indexed: 01/16/2023]
Abstract
Adipose tissue-derived stromal cells (ASCs) are of interest in tissue engineering and regenerative medicine (TERM) due to their easy acquisition, multipotency, and secretion of a host of factors that promote regeneration. Retention of ASCs in or around lesions is poor following direct administration. Therefore, for TERM applications, ASCs can be ‘immobilized’ via their incorporation into hydrogels such as gelatine methacryloyl (GelMA). Tweaking GelMA concentration is a common approach to approximate the mechanical properties found in organs or tissues that need repair. Distinct hydrogel mechanics influence the ability of a cell to spread, migrate, proliferate, and secrete trophic factors. Mesenchymal cells such as ASCs are potent remodellers of the extracellular matrix (ECM). Not only do ASCs deposit components, they also secrete matrix metalloproteases (MMPs) which degrade ECM. In this work, we investigated if GelMA polymer concentration influenced the expression of active MMPs by ASCs. In addition, MMPs’ presence was interrogated with regard to ASCs morphology and changes in hydrogel ultrastructure. For this, immortalised ASCs were embedded in 5%, 10%, and 15% (w/v) GelMA hydrogels, photopolymerised and cultured for 14 d. Zymography in situ indicated that MMPs had a variable, hydrogel concentration-dependent influence on ASCs-secreted MMPs. In 5% GelMA, ASCs showed a high and sustained expression of MMPs, while, in 10% and 15% GelMA, such expression was almost null. ASCs morphology based on F-actin staining showed that increasing GelMA concentrations inhibit their spreading. Scanning electron microscopy (SEM) showed that hydrogel ultrastructure in terms of pore density, pore size, and percentage porosity were not consistently influenced by cells. Interestingly, changes in ultrastructural parameters were detected also in cell-free materials, albeit without a clear trend. We conclude that hydrogel concentration and its underlying mechanics influenced MMP expression by ASCs. The exact MMPs that respond to these mechanical cues should be defined in follow-up experiments.
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Affiliation(s)
- Francisco Drusso Martinez-Garcia
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (F.D.M.-G.); (J.K.B.)
- W.J. Kolff Research Institute, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Joris Anton van Dongen
- Department of Plastic Surgery, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
| | - Janette Kay Burgess
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (F.D.M.-G.); (J.K.B.)
- W.J. Kolff Research Institute, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
- Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Martin Conrad Harmsen
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (F.D.M.-G.); (J.K.B.)
- W.J. Kolff Research Institute, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
- Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
- Correspondence:
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Role and Function of Mesenchymal Stem Cells on Fibroblast in Cutaneous Wound Healing. Biomedicines 2022; 10:biomedicines10061391. [PMID: 35740413 PMCID: PMC9219688 DOI: 10.3390/biomedicines10061391] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/06/2022] [Accepted: 06/10/2022] [Indexed: 11/24/2022] Open
Abstract
Skin wounds often repair themselves completely over time; however, this is true only for healthy individuals. Although various studies are being conducted to improve wound-healing therapy outcomes, the mechanisms of wound healing and regeneration are not completely understood yet. In recent years, mesenchymal stem cells (MSCs) have been reported to contribute significantly to wound healing and regeneration. Understanding the function of MSCs will help to elucidate the fundamentals of wound healing. MSCs are multipotent stem cells that are used in regenerative medicine for their ability to self-renew and differentiate into bone, fat, and cartilage, with few ethical problems associated with cell harvesting. Additionally, they have anti-inflammatory and immunomodulatory properties and antifibrotic effects via paracrine signaling, and many studies have been conducted to use them to treat graft-versus-host disease, inflammatory bowel disease, and intractable cutaneous wounds. Many substances derived from MSCs are involved in the wound-healing process, and specific cascades and pathways have been elucidated. This review aims to explain the fundamental role of MSCs in wound healing and the effects of MSCs on fibroblasts.
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Peng Q, Ren G, Xuan Z, Duda M, Pennisi CP, Porsborg SR, Fink T, Zachar V. Distinct Dominant Lineage from In Vitro Expanded Adipose-Derived Stem Cells (ASCs) Exhibits Enhanced Wound Healing Properties. Cells 2022; 11:cells11071236. [PMID: 35406800 PMCID: PMC8998068 DOI: 10.3390/cells11071236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/03/2022] [Accepted: 04/04/2022] [Indexed: 12/16/2022] Open
Abstract
It has been suggested that immunophenotypically defined lineages within the in vitro expanded adipose-derived stem cell (ASC) may play a beneficial role from the perspective of a personalized intervention. Therefore, to better understand the implications of different surface marker profiles for the functionality, we set out to examine the evolution of ASC-variants based on the co-expression of five bright or eight dim epitopes. At passages P1, P4, and P8, the co-localization of five bright markers (CD73, CD90, CD105, CD166, and CD201), or eight dim markers (CD34, CD36, CD200, CD248, CD271, CD274, CD146, and the Stro-1), was investigated by flow cytometry. Selected subpopulations were isolated using the fluorescence-activated cells sorting from the cryopreserved P4 and analyzed in terms of proliferative and clonogenic properties, trilineage differentiation, and wound healing potential. Only two of the dim epitopes were found in representative subpopulations (SP), and from the P4 onwards, two major combinations featuring the CD274+ (SP1) or the CD274+ CD146+ (SP2) emerged. Upon sorting and growth, both subpopulations assumed new but highly similar clonal profiles, consisting of the CD274+ CD146+ and the CD274+ CD146+ CD248+ phenotypes. The functional analysis revealed that the SP2 surpassed SP1 and the unfractionated cells regarding the growth rate, clonogenic activity, and the wound closure and endothelial tube formation potential. The surface epitopes may be considered a tool to enrich specific functionality and thus improve therapeutic outcomes in dedicated circumstances.
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Zuccarini M, Giuliani P, Di Liberto V, Frinchi M, Caciagli F, Caruso V, Ciccarelli R, Mudò G, Di Iorio P. Adipose Stromal/Stem Cell-Derived Extracellular Vesicles: Potential Next-Generation Anti-Obesity Agents. Int J Mol Sci 2022; 23:ijms23031543. [PMID: 35163472 PMCID: PMC8836090 DOI: 10.3390/ijms23031543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/26/2022] [Accepted: 01/26/2022] [Indexed: 02/01/2023] Open
Abstract
Over the last decade, several compounds have been identified for the treatment of obesity. However, due to the complexity of the disease, many pharmacological interventions have raised concerns about their efficacy and safety. Therefore, it is important to discover new factors involved in the induction/progression of obesity. Adipose stromal/stem cells (ASCs), which are mostly isolated from subcutaneous adipose tissue, are the primary cells contributing to the expansion of fat mass. Like other cells, ASCs release nanoparticles known as extracellular vesicles (EVs), which are being actively studied for their potential applications in a variety of diseases. Here, we focused on the importance of the contribution of ASC-derived EVs in the regulation of metabolic processes. In addition, we outlined the advantages/disadvantages of the use of EVs as potential next-generation anti-obesity agents.
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Affiliation(s)
- Mariachiara Zuccarini
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (M.Z.); (P.G.); (P.D.I.)
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy;
| | - Patricia Giuliani
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (M.Z.); (P.G.); (P.D.I.)
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy;
| | - Valentina Di Liberto
- Department of Biomedicine, Neuroscience and Advanced Diagnostic, University of Palermo, 90128 Palermo, Italy; (V.D.L.); (M.F.); (G.M.)
| | - Monica Frinchi
- Department of Biomedicine, Neuroscience and Advanced Diagnostic, University of Palermo, 90128 Palermo, Italy; (V.D.L.); (M.F.); (G.M.)
| | - Francesco Caciagli
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy;
| | - Vanni Caruso
- School of Pharmacy and Pharmacology, University of Tasmania, Hobart 7001, Australia;
| | - Renata Ciccarelli
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (M.Z.); (P.G.); (P.D.I.)
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy;
- Stem TeCh Group, Center for Advanced Studies and Technologies (CAST), Via L. Polacchi, 66100 Chieti, Italy
- Correspondence:
| | - Giuseppa Mudò
- Department of Biomedicine, Neuroscience and Advanced Diagnostic, University of Palermo, 90128 Palermo, Italy; (V.D.L.); (M.F.); (G.M.)
| | - Patrizia Di Iorio
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (M.Z.); (P.G.); (P.D.I.)
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100 Chieti, Italy;
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Al-Ghadban S, Artiles M, Bunnell BA. Adipose Stem Cells in Regenerative Medicine: Looking Forward. Front Bioeng Biotechnol 2022; 9:837464. [PMID: 35096804 PMCID: PMC8792599 DOI: 10.3389/fbioe.2021.837464] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 12/27/2021] [Indexed: 12/16/2022] Open
Abstract
Over the last decade, stem cell-based regenerative medicine has progressed to clinical testing and therapeutic applications. The applications range from infusions of autologous and allogeneic stem cells to stem cell-derived products. Adult stem cells from adipose tissue (ASCs) show significant promise in treating autoimmune and neurodegenerative diseases, vascular and metabolic diseases, bone and cartilage regeneration and wound defects. The regenerative capabilities of ASCs in vivo are primarily orchestrated by their secretome of paracrine factors and cell-matrix interactions. More recent developments are focused on creating more complex structures such as 3D organoids, tissue elements and eventually fully functional tissues and organs to replace or repair diseased or damaged tissues. The current and future applications for ASCs in regenerative medicine are discussed here.
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Affiliation(s)
| | | | - Bruce A. Bunnell
- Department of Microbiology Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
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Labarre KW, Zimmermann G. Infiltration of the Hoffa's fat pad in patients with osteoarthritis of the knee-Results after one year of follow-up. Bone Rep 2022; 16:101168. [PMID: 35733948 PMCID: PMC9207720 DOI: 10.1016/j.bonr.2022.101168] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/12/2022] [Accepted: 01/18/2022] [Indexed: 12/15/2022] Open
Abstract
Objectives Cell therapy using multipotential stromal cells (MSCs) is being used in a variety of clinical settings to induce tissue regeneration. Promising results have also been achieved in the therapy of osteoarthritis. MSCs have been demonstrated to be safe (Borakati et al., 2018). They can be used in a one step procedure as minimally manipulated mesenchymal stem cells or after in vitro expansion. The in vitro step allows for the selection of a more homogeneous cell population, meeting the standard criteria for MSC identification (Lv et al., 2014). In vitro expansion of MSCs is cost intensive, time consuming and furthermore associated with gradual accumulation of senescent cells (Wagner et al., 2008), telomere erosion (Baxter et al., 2004), and changing phenotypes (Jones et al., 2010; Halfon et al., 2011). These disadvantages could be surpassed by the use of “minimally manipulated mesenchymal stem cells” from bone marrow or adipose tissue (Di Matteo et al., 2019) such as the adipogenic stromal-vascular fraction (SVF). The study investigates whether infiltration of the Hoffa fat pad with autologous SVF is an effective and safe treatment option for patients with gonarthrosis. Furthermore, the number and vitality of the injected cells as well as the clinical efficacy will be evaluated. Materials and methods We conduct a prospective study. Patients with osteoarthritis of the knee receive infiltration of SVF into the Hoffa fat pad. The number and vitality of the cells are measured with a cell counter. The clinical outcome is checked using VAS, KOOS and SF12 questionnaires with a follow-up period of 1 year. Results A total of 33 patients and 36 knees were included in this Study. An average of 45 million cells were injected with a standard deviation of 2,5 million Cells. After 6 months a significant improvement of the VAS and the respective subscales of the KOOS could be observed compared to the baseline. After one year of follow-up, a significant improvement in all KOOS subscales compared to baseline was still observed. A significant correlation between reduced knee pain on the VAS and the number of injected cells could be observed as well. Thus, patients injected with a higher number of cells seem to have a better outcome. The average viability of the cells was 64,4% with a standard deviation of 15,9%. A correlation between higher cell viability and better outcome on the QOL subscale of the KOOS was observed. There were no major complications or side effects. Discussion These initial results indicate that treatment with SVF is a safe therapeutic option that has the potential to relieve joint pain and significantly improved function. The cell number and vitality of the injected cells appear to be important factors influencing the success of the therapy.
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Wang L, Wang X, Liang R, Wang S, Cao J. A Comparison of Mesenchymal Stem Cells from Human Adipose Tissues by Resection and by Liposuction. J HARD TISSUE BIOL 2022. [DOI: 10.2485/jhtb.31.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Le Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University
| | - Xingqiang Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University
| | - Rui Liang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University
| | - Jinglin Cao
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University
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Milan G, Conci S, Sanna M, Favaretto F, Bettini S, Vettor R. ASCs and their role in obesity and metabolic diseases. Trends Endocrinol Metab 2021; 32:994-1006. [PMID: 34625375 DOI: 10.1016/j.tem.2021.09.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/23/2021] [Accepted: 09/03/2021] [Indexed: 01/04/2023]
Abstract
We describe adipose stromal/stem cells (ASCs) in the structural/functional context of the adipose tissue (AT) stem niche (adiponiche), including cell-cell interactions and the microenvironment, and emphasize findings obtained in humans and in lineage-tracing models. ASCs have distinctive markers, 'colors', and anatomical 'locations' which influence their functions. Each adiponiche component can become impaired, thereby contributing to the pathological AT alterations seen in obesity and metabolic diseases. We discuss adiposopathy with a focus on adiponiche dysfunction, and underline the mechanisms that control AT expansion and energy balance. Better understanding of adiponiche regulation and ASC features could help to identify therapeutic targets that favor weight loss and counteract weight regain, and also contribute to innovative strategies for regenerative medicine.
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Affiliation(s)
- Gabriella Milan
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy.
| | - Scilla Conci
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
| | - Marta Sanna
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
| | - Francesca Favaretto
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
| | - Silvia Bettini
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
| | - Roberto Vettor
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
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Identification and characterization of murine adipose tissue-derived somatic stem cells of Shenque (CV8) acupoint. Chin Med J (Engl) 2021; 134:2730-2737. [PMID: 34732664 PMCID: PMC8631409 DOI: 10.1097/cm9.0000000000001850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background: Shenque (CV8) acupoint is located on the navel and has been therapeutically used for more than 2000 years in Traditional Chinese Medicine (TCM). However, clinical research on the underlying therapeutic molecular mechanisms of the CV8 acupoint lags far behind. This study aimed to study the mechanisms of umbilical acupoint therapy by using stem cells. Methods: The morphological characteristics of CV8 acupoint were detected under a stereomicroscope using hematoxylin and eosin (H&E) staining. Oil Red, Masson, and immunohistochemical staining on multi-layered slices were used to identify the type of cells at the CV8 acupoint. Cell proliferation was measured by a cell counting kit-8 (CCK-8) method. Flow cytometry and immunohistochemistry were used for cell identification. Induced differentiation was used to compare the differentiation of cells derived from CV8 acupoint and non-acupoint somatic stem cells into other cell types, such as osteogenic, adipogenic, and neural stem cell-like cells. Results: Morphological observations showed that adipose tissues at the linea alba of the CV8 acupoint in mice had a mass-like distribution. Immunohistochemical staining confirmed the distribution of stem cell antigen-1 (Sca-1) positive cells in the multi-layered slices of CV8 acupoint tissues. Cells isolated from adipose tissues at the CV8 acupoint exhibited high expression of Sca-1 and CD44 and low expression of CD31 and CD34, and these cells possessed osteogenic, adipogenic, and neurogenic stem cell-like cell differentiation ability. The cell proliferation (day 4: 0.5138 ± 0.0111 vs. 0.4107 ± 0.0180, t = 8.447, P = 0.0011; day 5: 0.6890 ± 0.0070 vs. 0.5520 ± 0.0118, t = 17.310, P < 0.0001; day 6: 0.7320 ± 0.0090 vs. 0.6157 ± 0.0123, t = 13.190, P = 0.0002; and day 7: 0.7550 ± 0.0050 vs. 0.6313 ± 0.0051, t = 42.560, P < 0.0001), adipogenic ([9.224 ± 0.345]% vs. [3.933 ± 1.800]%, t = 5.000, P = 0.0075), and neurogenic stem cell-like cell differentiation (diameter < 50 μm: 7.2000 ± 1.3040 vs. 2.6000 ± 0.5477, t = 7.273, P < 0.0001; diameter 50–100 μm: 2.6000 ± 0.5477 vs. 1.0000 ± 0.7071, t = 4.000, P = 0.0039; and diameter >100 μm: 2.6000 ± 0.5477 vs. 0.8000 ± 0.8367, t = 4.025, P = 0.0038) were significantly enhanced in somatic stem cells derived from the CV8 acupoint compared to somatic stem cells from the groin non-acupoint. However, cells possessed significantly weaker osteogenicity ([2.697 ± 0.627]% vs. [7.254 ± 0.958]%, t = 6.893, P = 0.0023) in the CV8 acupoint group. Conclusions: Our study showed that CV8 acupoint was rich with adipose tissues that contained abundant somatic stem cells. The biological examination of somatic stem cells derived from the CV8 acupoint provided novel insights for future research on the mechanisms of umbilical therapy.
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Perucca Orfei C, Bowles AC, Kouroupis D, Willman MA, Ragni E, Kaplan LD, Best TM, Correa D, de Girolamo L. Human Tendon Stem/Progenitor Cell Features and Functionality Are Highly Influenced by in vitro Culture Conditions. Front Bioeng Biotechnol 2021; 9:711964. [PMID: 34616717 PMCID: PMC8488466 DOI: 10.3389/fbioe.2021.711964] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/26/2021] [Indexed: 01/09/2023] Open
Abstract
Our understanding of tendon biology continues to evolve, thus leading to opportunities for developing novel, evidence-based effective therapies for the treatment of tendon disorders. Implementing the knowledge of tendon stem/progenitor cells (TSPCs) and assessing their potential in enhancing tendon repair could fill an important gap in this regard. We described different molecular and phenotypic profiles of TSPCs modulated by culture density, as well as their multipotency and secretory activities. Moreover, in the same experimental setting, we evaluated for different responses to inflammatory stimuli mediated by TNFα and IFNγ. We also preliminarily investigated their immunomodulatory activity and their role in regulating degradation of substance P. Our findings indicated that TSPCs cultured at low density (LD) exhibited cobblestone morphology and a reduced propensity to differentiate. A distinctive immunophenotypic profile was also observed with high secretory and promising immunomodulatory responses when primed with TNFα and IFNγ. In contrast, TSPCs cultured at high density (HD) showed a more elongated fibroblast-like morphology, a greater adipogenic differentiation potential, and a higher expression of tendon-related genes with respect to LD. Finally, HD TSPCs showed immunomodulatory potential when primed with TNFα and IFNγ, which was slightly lower than that shown by LD. A shift from low to high culture density during TSPC expansion demonstrated intermediate features confirming the cellular adaptability of TSPCs. Taken together, these experiments allowed us to identify relevant differences in TSPCs based on culture conditions. This ability of TSPCs to acquire distinguished morphology, phenotype, gene expression profile, and functional response advances our current understanding of tendons at a cellular level and suggests responsivity to cues in their in situ microenvironment.
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Affiliation(s)
- Carlotta Perucca Orfei
- Laboratorio di Biotecnologie Applicate all'Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Annie C Bowles
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, Miami, FL, United States.,Diabetes Research Institute and Cell Transplantation Center, University of Miami, Miller School of Medicine, Miami, FL, United States.,Department of Biomedical Engineering College of Engineering, University of Miami, Miami, FL, United States
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, Miami, FL, United States.,Diabetes Research Institute and Cell Transplantation Center, University of Miami, Miller School of Medicine, Miami, FL, United States
| | - Melissa A Willman
- Diabetes Research Institute and Cell Transplantation Center, University of Miami, Miller School of Medicine, Miami, FL, United States
| | - Enrico Ragni
- Laboratorio di Biotecnologie Applicate all'Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Lee D Kaplan
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, Miami, FL, United States
| | - Thomas M Best
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, Miami, FL, United States
| | - Diego Correa
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, Miami, FL, United States.,Diabetes Research Institute and Cell Transplantation Center, University of Miami, Miller School of Medicine, Miami, FL, United States
| | - Laura de Girolamo
- Laboratorio di Biotecnologie Applicate all'Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
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Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery. Nat Commun 2021; 12:5006. [PMID: 34408135 PMCID: PMC8373975 DOI: 10.1038/s41467-021-25333-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 08/03/2021] [Indexed: 12/30/2022] Open
Abstract
Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored. Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease. Obesity is a major risk factor for cancer related death. Here, the authors show that visceral adipose-derived factors promote vasculogenesis and metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming colorectal cancer cells into a highly metastatic phenotype.
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Deptuła M, Brzezicka A, Skoniecka A, Zieliński J, Pikuła M. Adipose-derived stromal cells for nonhealing wounds: Emerging opportunities and challenges. Med Res Rev 2021; 41:2130-2171. [PMID: 33522005 PMCID: PMC8247932 DOI: 10.1002/med.21789] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/30/2020] [Accepted: 01/20/2021] [Indexed: 12/21/2022]
Abstract
Wound healing complications affect thousands of people each year, thus constituting a profound economic and medical burden. Chronic wounds are a highly complex problem that usually affects elderly patients as well as patients with comorbidities such as diabetes, cancer (surgery, radiotherapy/chemotherapy) or autoimmune diseases. Currently available methods of their treatment are not fully effective, so new solutions are constantly being sought. Cell-based therapies seem to have great potential for use in stimulating wound healing. In recent years, much effort has been focused on characterizing of adipose-derived mesenchymal stromal cells (AD-MSCs) and evaluating their clinical use in regenerative medicine and other medical fields. These cells are easily obtained in large amounts from adipose tissue and show a high proregenerative potential, mainly through paracrine activities. In this review, the process of healing acute and nonhealing (chronic) wounds is detailed, with a special attention paid to the wounds of patients with diabetes and cancer. In addition, the methods and technical aspects of AD-MSCs isolation, culture and transplantation in chronic wounds are described, and the characteristics, genetic stability and role of AD-MSCs in wound healing are also summarized. The biological properties of AD-MSCs isolated from subcutaneous and visceral adipose tissue are compared. Additionally, methods to increase their therapeutic potential as well as factors that may affect their biological functions are summarized. Finally, their therapeutic potential in the treatment of diabetic and oncological wounds is also discussed.
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Affiliation(s)
- Milena Deptuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Department of EmbryologyMedical University of GdanskGdańskPoland
| | | | - Aneta Skoniecka
- Department of Embryology, Faculty of MedicineMedical University of GdanskGdańskPoland
| | - Jacek Zieliński
- Department of Oncologic SurgeryMedical University of GdanskGdańskPoland
| | - Michał Pikuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Department of EmbryologyMedical University of GdanskGdańskPoland
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Herbrich S, Baran N, Cai T, Weng C, Aitken MJL, Post SM, Henderson J, Shi C, Richard-Carpentier G, Sauvageau G, Baggerly K, Al-Atrash G, Davis RE, Daver N, Zha D, Konopleva M. Overexpression of CD200 is a Stem Cell-Specific Mechanism of Immune Evasion in AML. J Immunother Cancer 2021; 9:e002968. [PMID: 34326171 PMCID: PMC8323398 DOI: 10.1136/jitc-2021-002968] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) stem cells (LSCs) are capable of surviving current standard chemotherapy and are the likely source of deadly, relapsed disease. While stem cell transplant serves as proof-of-principle that AML LSCs can be eliminated by the immune system, the translation of existing immunotherapies to AML has been met with limited success. Consequently, understanding and exploiting the unique immune-evasive mechanisms of AML LSCs is critical. METHODS Analysis of stem cell datasets and primary patient samples revealed CD200 as a putative stem cell-specific immune checkpoint overexpressed in AML LSCs. Isogenic cell line models of CD200 expression were employed to characterize the interaction of CD200+ AML with various immune cell subsets both in vitro and in peripheral blood mononuclear cell (PBMC)-humanized mouse models. CyTOF and RNA-sequencing were performed on humanized mice to identify novel mechanisms of CD200-mediated immunosuppression. To clinically translate these findings, we developed a fully humanized CD200 antibody (IgG1) that removed the immunosuppressive signal by blocking interaction with the CD200 receptor while also inducing a potent Fc-mediated response. Therapeutic efficacy of the CD200 antibody was evaluated using both humanized mice and patient-derived xenograft models. RESULTS Our results demonstrate that CD200 is selectively overexpressed in AML LSCs and is broadly immunosuppressive by impairing cytokine secretion in both innate and adaptive immune cell subsets. In a PBMC-humanized mouse model, CD200+ leukemia progressed rapidly, escaping elimination by T cells, compared with CD200- AML. T cells from mice with CD200+ AML were characterized by an abundance of metabolically quiescent CD8+ central and effector memory cells. Mechanistically, CD200 expression on AML cells significantly impaired OXPHOS metabolic activity in T cells from healthy donors. Importantly, CD200 antibody therapy could eliminate disease in the presence of graft-versus-leukemia in immune competent mice and could significantly improve the efficacy of low-intensity azacitidine/venetoclax chemotherapy in immunodeficient hosts. CONCLUSIONS Overexpression of CD200 is a stem cell-specific marker that contributes to immunosuppression in AML by impairing effector cell metabolism and function. CD200 antibody therapy is capable of simultaneously reducing CD200-mediated suppression while also engaging macrophage activity. This study lays the groundwork for CD200-targeted therapeutic strategies to eliminate LSCs and prevent AML relapse.
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Affiliation(s)
- Shelley Herbrich
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Natalia Baran
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Tianyu Cai
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Connie Weng
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Marisa J L Aitken
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sean M Post
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jared Henderson
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Chunhua Shi
- Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Guy Sauvageau
- University of Montreal Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada
| | - Keith Baggerly
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Gheath Al-Atrash
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - R Eric Davis
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Naval Daver
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dongxing Zha
- Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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46
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Slaughter VL, Rumsey JW, Boone R, Malik D, Cai Y, Sriram NN, Long CJ, McAleer CW, Lambert S, Shuler ML, Hickman JJ. Validation of an adipose-liver human-on-a-chip model of NAFLD for preclinical therapeutic efficacy evaluation. Sci Rep 2021; 11:13159. [PMID: 34162924 PMCID: PMC8222323 DOI: 10.1038/s41598-021-92264-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/08/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and strongly correlates with the growing incidence of obesity and type II diabetes. We have developed a human-on-a-chip model composed of human hepatocytes and adipose tissue chambers capable of modeling the metabolic factors that contribute to liver disease development and progression, and evaluation of the therapeutic metformin. This model uses a serum-free, recirculating medium tailored to represent different human metabolic conditions over a 14-day period. The system validated the indirect influence of adipocyte physiology on hepatocytes that modeled important aspects of NAFLD progression, including insulin resistant biomarkers, differential adipokine signaling in different media and increased TNF-α-induced steatosis observed only in the two-tissue model. This model provides a simple but unique platform to evaluate aspects of an individual factor's contribution to NAFLD development and mechanisms as well as evaluate preclinical drug efficacy and reassess human dosing regimens.
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Affiliation(s)
- Victoria L Slaughter
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826, USA
| | - John W Rumsey
- Hesperos, Inc., 12501 Research Parkway, Suite 100, Orlando, FL, 32826, USA
| | - Rachel Boone
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826, USA
| | - Duaa Malik
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826, USA
| | - Yunqing Cai
- Hesperos, Inc., 12501 Research Parkway, Suite 100, Orlando, FL, 32826, USA
| | | | - Christopher J Long
- Hesperos, Inc., 12501 Research Parkway, Suite 100, Orlando, FL, 32826, USA
| | | | - Stephen Lambert
- College of Medicine, University of Central Florida, 6850 Lake Nona Blvd, Orlando, FL, 32827, USA
| | - Michael L Shuler
- Hesperos, Inc., 12501 Research Parkway, Suite 100, Orlando, FL, 32826, USA
| | - J J Hickman
- NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL, 32826, USA.
- Hesperos, Inc., 12501 Research Parkway, Suite 100, Orlando, FL, 32826, USA.
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Rahmani-Moghadam E, Zarrin V, Mahmoodzadeh A, Owrang M, Talaei-Khozani T. Comparison of the Characteristics of Breast Milk-derived Stem Cells with the Stem Cells Derived from the Other Sources: A Comparative Review. Curr Stem Cell Res Ther 2021; 17:71-90. [PMID: 34161214 DOI: 10.2174/1574888x16666210622125309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/14/2021] [Accepted: 03/28/2021] [Indexed: 11/22/2022]
Abstract
Breast milk (BrM) not only supplies nutrition, but it also contains a diverse population of cells. It has been estimated that up to 6% of the cells in human milk possess the characteristics of mesenchymal stem cells (MSC). Available data also indicate that these cells are multipotent and capable of self-renewal and differentiation with other cells. In this review, we have compared different characteristics, such as CD markers, differentiation capacity, and morphology of stem cells, derived from human breast milk (hBr-MSC) with human bone marrow (hBMSC), Wharton's jelly (WJMSC), and human adipose tissue (hADMSC). Through the literature review, it was revealed that human breast milk-derived stem cells specifically express a group of cell surface markers, including CD14, CD31, CD45, and CD86. Importantly, a group of markers, CD13, CD29, CD44, CD105, CD106, CD146, and CD166, were identified, which were common in the four sources of stem cells. WJMSC, hBMSC, hADMSC, and hBr-MSC are potently able to differentiate into the mesoderm, ectoderm, and endoderm cell lineages. The ability of hBr-MSCs todifferentiate into the neural stem cells, neurons, adipocyte, hepatocyte, chondrocyte, osteocyte, and cardiomyocytes has made these cells a promising source of stem cells in regenerative medicine, while isolation of stem cells from the commonly used sources, such as bone marrow, requires invasive procedures. Although autologous breast milk-derived stem cells are an accessible source for women who are in the lactation period, breast milk can be considered as a source of stem cells with high differentiation potential without any ethical concern.
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Affiliation(s)
- Ebrahim Rahmani-Moghadam
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahideh Zarrin
- Laboratory for Stem Cell Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Mahmoodzadeh
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Marzieh Owrang
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Ong WK, Chakraborty S, Sugii S. Adipose Tissue: Understanding the Heterogeneity of Stem Cells for Regenerative Medicine. Biomolecules 2021; 11:biom11070918. [PMID: 34206204 PMCID: PMC8301750 DOI: 10.3390/biom11070918] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/17/2021] [Accepted: 06/17/2021] [Indexed: 12/13/2022] Open
Abstract
Adipose-derived stem cells (ASCs) have been increasingly used as a versatile source of mesenchymal stem cells (MSCs) for diverse clinical investigations. However, their applications often become complicated due to heterogeneity arising from various factors. Cellular heterogeneity can occur due to: (i) nomenclature and criteria for definition; (ii) adipose tissue depots (e.g., subcutaneous fat, visceral fat) from which ASCs are isolated; (iii) donor and inter-subject variation (age, body mass index, gender, and disease state); (iv) species difference; and (v) study design (in vivo versus in vitro) and tools used (e.g., antibody isolation and culture conditions). There are also actual differences in resident cell types that exhibit ASC/MSC characteristics. Multilineage-differentiating stress-enduring (Muse) cells and dedifferentiated fat (DFAT) cells have been reported as an alternative or derivative source of ASCs for application in regenerative medicine. In this review, we discuss these factors that contribute to the heterogeneity of human ASCs in detail, and what should be taken into consideration for overcoming challenges associated with such heterogeneity in the clinical use of ASCs. Attempts to understand, define, and standardize cellular heterogeneity are important in supporting therapeutic strategies and regulatory considerations for the use of ASCs.
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Affiliation(s)
- Wee Kiat Ong
- School of Pharmacy, Monash University Malaysia, Subang Jaya 47500, Selangor, Malaysia
- Correspondence: (W.K.O.); (S.S.)
| | - Smarajit Chakraborty
- Institute of Bioengineering and Bioimaging (IBB), A*STAR, 31 Biopolis Way, Singapore 138669, Singapore;
| | - Shigeki Sugii
- Institute of Bioengineering and Bioimaging (IBB), A*STAR, 31 Biopolis Way, Singapore 138669, Singapore;
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
- Correspondence: (W.K.O.); (S.S.)
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Mikłosz A, Łukaszuk B, Supruniuk E, Grubczak K, Moniuszko M, Choromańska B, Myśliwiec P, Chabowski A. Does TBC1D4 (AS160) or TBC1D1 Deficiency Affect the Expression of Fatty Acid Handling Proteins in the Adipocytes Differentiated from Human Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Obtained from Subcutaneous and Visceral Fat Depots? Cells 2021; 10:1515. [PMID: 34208471 PMCID: PMC8235367 DOI: 10.3390/cells10061515] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/02/2021] [Accepted: 06/11/2021] [Indexed: 12/22/2022] Open
Abstract
TBC1D4 (AS160) and TBC1D1 are Rab GTPase-activating proteins that play a key role in the regulation of glucose and possibly the transport of long chain fatty acids (LCFAs) into muscle and fat cells. Knockdown (KD) of TBC1D4 increased CD36/SR-B2 and FABPpm protein expressions in L6 myotubes, whereas in murine cardiomyocytes, TBC1D4 deficiency led to a redistribution of CD36/SR-B2 to the sarcolemma. In our study, we investigated the previously unexplored role of both Rab-GAPs in LCFAs uptake in human adipocytes differentiated from the ADMSCs of subcutaneous and visceral adipose tissue origin. To this end we performed a single- and double-knockdown of the proteins (TBC1D1 and TBC1D4). Herein, we provide evidence that AS160 mediates fatty acid entry into the adipocytes derived from ADMSCs. TBC1D4 KD resulted in quite a few alterations to the cellular phenotype, the most obvious of which was the shift of the CD36/SR-B2 transport protein to the plasma membrane. The above translated into an increased uptake of saturated long-chain fatty acid. Interestingly, we observed a tissue-specific pattern, with more pronounced changes present in the adipocytes derived from subADMSCs. Altogether, our data show that in human adipocytes, TBC1D4, but not TBC1D1, deficiency increases LCFAs transport via CD36/SR-B2 translocation.
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Affiliation(s)
- Agnieszka Mikłosz
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (B.Ł.); (E.S.); (A.C.)
| | - Bartłomiej Łukaszuk
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (B.Ł.); (E.S.); (A.C.)
| | - Elżbieta Supruniuk
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (B.Ł.); (E.S.); (A.C.)
| | - Kamil Grubczak
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Waszyngtona 13 Street, 15-269 Bialystok, Poland; (K.G.); (M.M.)
| | - Marcin Moniuszko
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Waszyngtona 13 Street, 15-269 Bialystok, Poland; (K.G.); (M.M.)
| | - Barbara Choromańska
- Department of General and Endocrine Surgery, Medical University of Bialystok, M. Sklodowskiej-Curie 24a Street, 15-276 Bialystok, Poland; (B.C.); (P.M.)
| | - Piotr Myśliwiec
- Department of General and Endocrine Surgery, Medical University of Bialystok, M. Sklodowskiej-Curie 24a Street, 15-276 Bialystok, Poland; (B.C.); (P.M.)
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2C Street, 15-222 Bialystok, Poland; (B.Ł.); (E.S.); (A.C.)
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Crohn's Disease Increases the Mesothelial Properties of Adipocyte Progenitors in the Creeping Fat. Int J Mol Sci 2021; 22:ijms22084292. [PMID: 33924264 PMCID: PMC8074767 DOI: 10.3390/ijms22084292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/13/2021] [Accepted: 04/16/2021] [Indexed: 12/14/2022] Open
Abstract
Our understanding of the interplay between human adipose tissue and the immune system is limited. The mesothelium, an immunologically active structure, emerged as a source of visceral adipose tissue. After investigating the mesothelial properties of human visceral and subcutaneous adipose tissue and their progenitors, we explored whether the dysfunctional obese and Crohn's disease environments influence the mesothelial/mesenchymal properties of their adipocyte precursors, as well as their ability to mount an immune response. Using a tandem transcriptomic/proteomic approach, we evaluated the mesothelial and mesenchymal expression profiles in adipose tissue, both in subjects covering a wide range of body-mass indexes and in Crohn's disease patients. We also isolated adipose tissue precursors (adipose-derived stem cells, ASCs) to assess their mesothelial/mesenchymal properties, as well as their antigen-presenting features. Human visceral tissue presented a mesothelial phenotype not detected in the subcutaneous fat. Only ASCs from mesenteric adipose tissue, named creeping fat, had a significantly higher expression of the hallmark mesothelial genes mesothelin (MSLN) and Wilms' tumor suppressor gene 1 (WT1), supporting a mesothelial nature of these cells. Both lean and Crohn's disease visceral ASCs expressed equivalent surface percentages of the antigen-presenting molecules human leucocyte antigen-DR isotype (HLA-DR) and CD86. However, lean-derived ASCs were predominantly HLA-DR dim, whereas in Crohn's disease, the HLA-DR bright subpopulation was increased 3.2-fold. Importantly, the mesothelial-enriched Crohn's disease precursors activated CD4+ T-lymphocytes. Our study evidences a mesothelial signature in the creeping fat of Crohn's disease patients and its progenitor cells, the latter being able to present antigens and orchestrate an immune response.
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