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Dembitz V, James SC, Gallipoli P. Targeting lipid metabolism in acute myeloid leukemia: biological insights and therapeutic opportunities. Leukemia 2025:10.1038/s41375-025-02645-z. [PMID: 40404984 DOI: 10.1038/s41375-025-02645-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 05/05/2025] [Accepted: 05/12/2025] [Indexed: 05/24/2025]
Abstract
Metabolic rewiring is a hallmark of malignant transformation in leukemic cells and the potential offered by its therapeutic targeting has garnered significant attention. The development of clinically relevant metabolic targeted therapies in acute myeloid leukemia (AML) has mostly focused on targeting mitochondrial energy production, but progress has been hampered by generalized toxicities. An alternative strategy is to shift the focus from targeting energy production to targeting more specialized metabolic functions, such as energy storage, the regulation of oxidative stress and availability of cofactors needed for the function of specific metabolic reactions. Lipid metabolism plays a role in many of these metabolic functions and its importance in AML maintenance and response to therapy is being increasingly recognized but needs to be adequately interpreted in the context of its interaction with the microenvironment, particularly the adipose niche. In this review, we provide an overview of our current understanding of AML cellular metabolic dependencies on fatty acid and lipid metabolism and discuss their relevance in the context of functional interactions with adipocytes. We highlight unresolved questions about how to best target lipid metabolism and suggest approaches needed to fully understand the interplay between malignant cells and their niche in the context of metabolic dependencies.
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Affiliation(s)
- Vilma Dembitz
- Department of Physiology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Sophie C James
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Paolo Gallipoli
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
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2
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Muratoğlu B, Özdemir C, Eylem CC, Reçber T, Nemutlu E, Yet İ, Uçkan-Çetinkaya D. Circadian rhythm and aryl hydrocarbon receptor crosstalk in bone marrow adipose tissue and implications in leukemia. Sci Rep 2025; 15:16387. [PMID: 40350529 PMCID: PMC12066725 DOI: 10.1038/s41598-025-93169-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 03/05/2025] [Indexed: 05/14/2025] Open
Abstract
Leukemic cells modulate the bone marrow microenvironment to enhance their survival. Lipolysis in bone marrow adipose tissue (BMAT) has emerged as a critical factor supporting leukemic cell survival, yet understanding its primary role in leukemia development remains limited. Fanconi anemia (FA), characterized by a predisposition to acute myeloid leukemia (AML) and hypersensitivity to environmental toxins, is a transitional model for studying leukemic transformation. İntegrated multi-omics analyses were conducted on BMAT-derived mesenchymal stem/stromal cells (MSCs) from healthy donors (HD), AML, and FA patients. These analyses revealed intricate interactions among genes, metabolites, and lipids. Particularly noteworthy were the effects observed following the inhibition of aryl hydrocarbon receptor (AhR) signaling by StemRegenin1 (SR1). BMAT-MSCs showed increased expression of epithelial-mesenchymal transition (EMT) genes in FA and AML, suggesting a potential shift towards cancer-associated fibroblasts in the dysregulated marrow microenvironment. Identification of potential circadian rhythm biomarkers (NPAS2, PER2, BHLHE40, PER3, CIART) in BMAT-MSCs indicates a link between related lipid metabolism genes (e.g., PTGS1, PIK3R1) and SR1 treatment, implicating them in lipolysis processes. Dysregulation of circadian rhythm-related genes (CIART, BHLHE40, NPAS2) in AML BMAT-MSCs, along with changes in circulating lipid metabolites like palmitate suggests their role in shaping the leukemia microenvironment. Upregulation of FABP5 and CD36 suggests a novel molecular mechanism involving FABP5 in AhR-mediated circadian regulation and identifies CD36 as a potential partner for FABP5 in BMAT-MSCs. Overall, this study unveils the interplay between AhR signaling, circadian rhythm, and the leukemia microenvironment in BMAT-MSCs, offering new insights into leukemia pathogenesis and therapeutic opportunities.
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Affiliation(s)
- Bihter Muratoğlu
- Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, 06100, Sihhiye, Ankara, Turkey
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, 06100, Sihhiye, Ankara, Turkey
| | - Cansu Özdemir
- Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, 06100, Sihhiye, Ankara, Turkey.
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, 06100, Sihhiye, Ankara, Turkey.
| | - Cemil Can Eylem
- Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Sihhiye, Ankara, Turkey
| | - Tuba Reçber
- Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Sihhiye, Ankara, Turkey
| | - Emirhan Nemutlu
- Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Sihhiye, Ankara, Turkey
| | - İdil Yet
- Department of Bioinformatics, Institute of Health Sciences, Hacettepe University, 06100, Sihhiye, Ankara, Turkey
| | - Duygu Uçkan-Çetinkaya
- Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, 06100, Sihhiye, Ankara, Turkey.
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, 06100, Sihhiye, Ankara, Turkey.
- Division of Hematology, Department of Pediatrics, Hacettepe University Faculty of Medicine, 06100, Sihhiye, Ankara, Turkey.
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3
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Feng J, Zhang M, Ren H, Ren Y, Hao Z, Bian S, Cui J, Li S, Xu J, Daniel MM, Ren F, Xu Z, Tan Y, Chen X, Zhang Y, Chang J, Wang H. Human umbilical cord mesenchymal stem cells improve bone marrow hematopoiesis through regulation of bone marrow adipose tissue. Mol Cell Biochem 2025; 480:3033-3049. [PMID: 39613944 PMCID: PMC12048464 DOI: 10.1007/s11010-024-05156-0] [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: 07/02/2024] [Accepted: 11/02/2024] [Indexed: 12/01/2024]
Abstract
Bone marrow adipose tissue (BMAT) exhibits a multitude of biological functionalities and influences hematopoiesis. The adiposity status of the bone marrow may play a role in the decline of hematopoietic function. Mesenchymal stem cells (MSCs) constitute crucial regulators within the bone marrow microenvironment; however, their precise role in modulating BMAT and the subsequent implications for hematopoiesis remain poorly understood. We conducted in vivo studies to observe the effects of human umbilical cord mesenchymal stem cells (hucMSCs) on BMAT accumulation and restoration of hematopoietic function in mice with drug-induced hematopoietic impairment. Concurrently, in vitro co-culture experiments were used to investigate the impact of hucMSCs on preadipocytes and mature adipocytes, and the potential subsequent consequences for hematopoietic cells. Moreover, we explored the potential mechanisms underlying these interactions. Our findings reveal that hucMSCs concomitantly mitigate BMAT accumulation and facilitate the recovery of hematopoietic function in mouse models with drug-induced hematopoietic impairment. In vitro, hucMSCs potentially impede adipogenic differentiation of 3T3-L1 preadipocytes through interference with the JAK2/STAT3 signaling pathway and affect the functionality of mature adipocytes, thus mitigating the detrimental effects of adipocytes on hematopoietic stem cells (HSCs). Furthermore, we demonstrate that hucMSCs may protect hematopoietic cells from adipocyte-induced damage by protecting antioxidative mechanisms. These results suggest that hucMSCs exhibit an inhibitory effect on the excessive expansion of adipose tissue and modulate adipose tissue function, which may potentially contribute to the regulation of the bone marrow microenvironment and favorably influence hematopoietic function improvement.
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Affiliation(s)
- Jingyi Feng
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
- The Second Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Miao Zhang
- The Second Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Huanying Ren
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Yan Ren
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Zhuanghui Hao
- The Second Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Sicheng Bian
- Department of Medicine, The MetroHealth System, Case Western Reserve University, Cleveland, OH, 44109, USA
| | - Jiangxia Cui
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Shuo Li
- The Second Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Jing Xu
- Department of Medical Cell Biology and Genetics, Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Muteb Muyey Daniel
- The Second Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Fanggang Ren
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Zhifang Xu
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Yanhong Tan
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Xiuhua Chen
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Yaofang Zhang
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Jianmei Chang
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China
| | - Hongwei Wang
- Institute of Hematology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China.
- The Second Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, People's Republic of China.
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4
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Poswal J, Mandal CC. Lipid metabolism dysregulation for bone metastasis and its prevention. Expert Rev Anticancer Ther 2025:1-17. [PMID: 40219980 DOI: 10.1080/14737140.2025.2492784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 04/06/2025] [Accepted: 04/09/2025] [Indexed: 04/14/2025]
Abstract
INTRODUCTION Bone metastasis often develops in advanced malignancies. Lipid metabolic dysregulation might play pivotal role in cancer progression and subsequent deterioration of bone health at metastatic condition. In-depth understanding of lipid reprogramming in metastasized cancer cells and other stromal cells including bone marrow adipocyte (BMA) is an urgent need to develop effective therapy. AREA COVERED This paper emphasizes providing an overview of multifaceted role of dysregulated lipids and BMA in cancer cells in association with bone metastasis by utilizing search terms lipid metabolism, lipid and metastasis in PubMed. This study extends to address mechanism linked with lipid metabolism and various crucial genes (e.g. CSF-1, RANKL, NFkB and NFATc1) involved in bone metastasis. This review examines therapeutic strategies targeting lipid metabolism to offer potential avenues to disrupt lipid-driven metastasis. EXPERT OPINION On metastatic condition, dysregulated lipid molecules especially in BMA and other stromal cells not only favors cancer progression but also potentiate lipid reprogramming within cancer cells. Distinct dysregulated lipid-metabolism associated genes may act as biomarker, and targeting these is challenging task for specific treatment. Curbing function of bone resorption associated genes by lipid controlling drugs (e.g. statins, omega-3 FA and metformin) may provide additional support to curtail lipid-associated bone metastasis.
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Affiliation(s)
- Jyoti Poswal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
| | - Chandi C Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
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Bessot A, Gunter J, McGovern J, Bock N. Bone marrow adipocytes in cancer: Mechanisms, models, and therapeutic implications. Biomaterials 2025; 322:123341. [PMID: 40315628 DOI: 10.1016/j.biomaterials.2025.123341] [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: 11/21/2024] [Revised: 04/02/2025] [Accepted: 04/12/2025] [Indexed: 05/04/2025]
Abstract
Adipose tissue is the primary site of energy storage in the body and a key regulator of metabolism. However, different adipose depots exhibit distinct molecular and phenotypic characteristics that have yet to be fully unraveled. While initially considered inert, bone marrow adipocytes (BMAs) have been recognized as key regulators of bone homeostasis, and more recently bone pathologies, although many unknowns remain. In this review, we summarize the current knowledge on BMAs, focusing on their distinct characteristics, functional significance in bone physiology and metabolism, as well as their emerging role in cancer pathogenesis. We present and discuss the current methodologies for investigating BMA-cancer interactions, encompassing both in vitro 3D culture systems and in vivo models, and their limitations in accurately replicating the phenotypes and biological processes of the human species. We highlight the imperative for advancing towards humanized models to better mimic the complexities of human physiology and disease progression. Finally, therapeutic strategies targeting metabolism or BMA-secreted factors, such as anti-cholesterol drugs, hold considerable promise in cancer treatment. We present the synergistic avenue of combining conventional cancer therapies with agents targeting adipocyte signaling to amplify treatment efficacy. Developing preclinical models that more faithfully replicate human pathological and physiological processes will lead to more accurate mechanistic understanding of the role of BMAs in bone metastasis and lead to more relevant preclinical drug screening.
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Affiliation(s)
- Agathe Bessot
- School of Biomedical Sciences, Faculty of Health, and Translational Research Institute (TRI), Queensland University of Technology (QUT), Brisbane, QLD, 4102, Australia; Centre for Biomedical Technologies, QUT, Brisbane, QLD, 4000, Australia; Max Planck Queensland Centre for the Materials Science of Extracellular Matrices, Brisbane, QLD, 4000, Australia
| | - Jennifer Gunter
- School of Biomedical Sciences, Faculty of Health, and Translational Research Institute (TRI), Queensland University of Technology (QUT), Brisbane, QLD, 4102, Australia; Australian Prostate Cancer Research Centre (APCRC-Q), QUT, Brisbane, QLD, 4102, Australia; Centre for Genomics and Personalised Health, QUT, Brisbane, QLD, 4102, Australia
| | - Jacqui McGovern
- School of Biomedical Sciences, Faculty of Health, and Translational Research Institute (TRI), Queensland University of Technology (QUT), Brisbane, QLD, 4102, Australia; Centre for Biomedical Technologies, QUT, Brisbane, QLD, 4000, Australia; Max Planck Queensland Centre for the Materials Science of Extracellular Matrices, Brisbane, QLD, 4000, Australia; Australian Research Council (ARC) Training Centre for Cell and Tissue Engineering Technologies (CTET), QUT, Brisbane, QLD, 4000, Australia
| | - Nathalie Bock
- School of Biomedical Sciences, Faculty of Health, and Translational Research Institute (TRI), Queensland University of Technology (QUT), Brisbane, QLD, 4102, Australia; Centre for Biomedical Technologies, QUT, Brisbane, QLD, 4000, Australia; Max Planck Queensland Centre for the Materials Science of Extracellular Matrices, Brisbane, QLD, 4000, Australia; Australian Prostate Cancer Research Centre (APCRC-Q), QUT, Brisbane, QLD, 4102, Australia; Australian Research Council (ARC) Training Centre for Multiscale 3D Imaging, Modelling, and Manufacturing (M3D Innovation), Queensland University of Technology, Brisbane, QLD, 4000, Australia.
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6
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Altea-Manzano P, Decker-Farrell A, Janowitz T, Erez A. Metabolic interplays between the tumour and the host shape the tumour macroenvironment. Nat Rev Cancer 2025; 25:274-292. [PMID: 39833533 DOI: 10.1038/s41568-024-00786-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/10/2024] [Indexed: 01/22/2025]
Abstract
Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.
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Affiliation(s)
| | | | | | - Ayelet Erez
- Weizmann Institute of Science, Rehovot, Israel.
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7
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Muratoğlu B, Özdemir C, Eylem CC, Reçber T, Nemutlu E, Alpdündar-Bulut E, Vargel İ, Uçkan-Çetinkaya D. Detailed characterization of bone marrow adipose tissue mesenchymal stem cells in healthy donor, Fanconi anemia, and acute myeloid leukemia. Bone 2025; 193:117413. [PMID: 39894290 DOI: 10.1016/j.bone.2025.117413] [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: 11/20/2024] [Revised: 01/08/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025]
Abstract
Bone marrow is a complex tissue featuring distinct cellular organization and diverse cell types. Bone marrow adipose tissue (BMAT) is a dynamic component crucial for tissue function and disease processes. This study explores differences between bone marrow-derived mesenchymal stem cells (BM-MSCs) and BMAT-derived mesenchymal stem cells (BMAT-MSCs), isolated from the same cavity, examining their differentiation potential and secretory profiles. BM-MSCs and BMAT-MSCs both exhibit classical mesenchymal characteristics, with over 90 % positivity for markers such as CD105 and CD29. Notably, BMAT-MSCs display significantly higher differentiation potential than BM-MSCs, with enhanced osteogenic and adipogenic capabilities, as indicated by increased calcium accumulation and lipid storage. In Fanconi anemia (FA) and acute myeloid leukemia (AML), osteogenic potential is limited, indicating impaired differentiation under these pathological conditions. Gene expression analysis of adipogenic molecules and metabolic regulators revealed significant differences in expression profile between BM- and BMAT-MSCs, particularly during adipogenic differentiation, indicating distinct characteristics that were more notable in FAs and AMLs. Furthermore, metabolomic profiling of BM plasma, using GC-MS for in-vivo niche reflection, and lipid analysis via LC-qTOF-MS show significant lipidomic alterations in patient samples, highlighting metabolic dysregulation and lipid remodeling. Lipid-mediated signaling and membrane composition changes appear integral to disease mechanisms. In conclusion, this study highlights the distinctive molecular and metabolomic profiles and adaptive mechanisms of BM- and BMAT-MSCs in bone marrow pathologies.
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Affiliation(s)
- Bihter Muratoğlu
- Institute of Health Sciences, Department of Stem Cell Sciences and Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Türkiye; Institute of Health Sciences, Department of Stem Cell Sciences, Hacettepe University, Ankara, Türkiye
| | - Cansu Özdemir
- Institute of Health Sciences, Department of Stem Cell Sciences and Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Türkiye; Institute of Health Sciences, Department of Stem Cell Sciences, Hacettepe University, Ankara, Türkiye.
| | - Cemil Can Eylem
- Department of Analytical Chemistry, Hacettepe University, Ankara, Türkiye
| | - Tuba Reçber
- Department of Analytical Chemistry, Hacettepe University, Ankara, Türkiye
| | - Emirhan Nemutlu
- Department of Analytical Chemistry, Hacettepe University, Ankara, Türkiye
| | - Esin Alpdündar-Bulut
- Institute of Health Sciences, Department of Stem Cell Sciences and Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Türkiye; Division of Hematology, Department of Pediatrics, Hacettepe University, Ankara, Türkiye
| | - İbrahim Vargel
- Faculty of Medicine, Department of Plastic, Reconstructive and Aesthetic Surgery, Hacettepe University, Ankara, Türkiye
| | - Duygu Uçkan-Çetinkaya
- Institute of Health Sciences, Department of Stem Cell Sciences and Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Türkiye; Institute of Health Sciences, Department of Stem Cell Sciences, Hacettepe University, Ankara, Türkiye; Division of Hematology, Department of Pediatrics, Hacettepe University, Ankara, Türkiye
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Zapata-Linares N, Toillon I, Wanherdrick K, Pigenet A, Duhalde F, Binvignat M, Martin-Uriz PS, Louvet L, Calleja-Cervantes ME, Ghali Mhenni O, Guibert C, Nourissat G, Nogier A, Leterme D, Broux O, Magneron P, Prosper F, Chauveau C, Landoulsi J, Berenbaum F, Rodriguez-Madoz JR, Lafage-Proust MH, Lucas S, Houard X. Implication of bone marrow adipose tissue in bone homeostasis during osteoarthritis. Osteoarthritis Cartilage 2025:S1063-4584(25)00870-2. [PMID: 40154729 DOI: 10.1016/j.joca.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 03/16/2025] [Accepted: 03/19/2025] [Indexed: 04/01/2025]
Abstract
OBJECTIVE To explore the role of bone marrow adipocytes (BMAds) in osteoarthritis (OA). METHODS Male and female C57BL/6 mice (n=4/group) underwent meniscectomy (MNX) or SHAM surgery. OA was determined using Osteoarthritis Research Society International (OARSI) score, and the number of perilipin+ adipocytes was quantified. Mesenchymal Stromal Cells (MSCs) from MNX and SHAM mice were differentiated into osteoblasts and adipocytes. Human adipocytes and MSCs (n=8) were enzymatically isolated from epiphyseal and metaphyseal marrow, and from subcutaneous adipose tissue (SCAT) of hip OA patients. Human OA MSCs were differentiated into osteoblasts and adipocytes (OA-Diff-hAdipo). Gene expression patterns of epiphyseal and metaphyseal BMAds, SCAT adipocytes and OA-Diff-hAdipo were evaluated by RNAseq (n=4). The effect conditioned media from OA epiphyseal bone (n=5) on the alkaline phosphatase (ALP) activity and mineralization kinetics was assessed in vitro. RESULTS Increase in BMAd density was positively correlated with cartilage degradation in MNX mice. OA modified the differentiation capacity of MSCs, accelerating adipocyte differentiation and failing to produce osteoblasts in both human and mice. Human epiphyseal, metaphyseal and SCAT adipocytes from the same OA patients each displayed a specific transcriptome, suggesting different functions. Enrichment analysis defined metaphyseal OA-BMAds as cells implicated in hematopoietic stem cell differentiation. On the other hand, epiphyseal OA-BMAds were considered as osteogenic cells showing an up-regulation of genes related to bone mineralization and remodeling. Specifically, OA epiphysis-secreted molecules decreased ALP activity and altered in vitro the mineralization process. CONCLUSION All these results support the emergence of BMAds as new cell partners in OA, opening new venues for therapeutic approaches.
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Affiliation(s)
- Natalia Zapata-Linares
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France
| | - Indira Toillon
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France
| | - Kristell Wanherdrick
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France
| | - Audrey Pigenet
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France
| | - Fanny Duhalde
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France; Sorbonne Université, CNRS, Laboratoire de Réactivité de Surface, LRS, F-75005, Paris, France
| | - Marie Binvignat
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France
| | | | - Loïc Louvet
- Marrow Adiposity and Bone Lab (MABLab) ULR4490, Université du Littoral Côte d'Opale, F-62200 Boulogne sur Mer, Univ. Lille, F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Maria E Calleja-Cervantes
- Hemato-Oncology Program. CIMA Universidad de Navarra-IdiSNA, Pamplona, Spain; Computational Biology Program, CIMA Universidad de Navarra-IdiSNA, Pamplona, Spain
| | - Olfa Ghali Mhenni
- Marrow Adiposity and Bone Lab (MABLab) ULR4490, Université du Littoral Côte d'Opale, F-62200 Boulogne sur Mer, Univ. Lille, F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Clément Guibert
- Sorbonne Université, CNRS, Laboratoire de Réactivité de Surface, LRS, F-75005, Paris, France
| | - Geoffroy Nourissat
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France
| | | | - Damien Leterme
- Marrow Adiposity and Bone Lab (MABLab) ULR4490, Université du Littoral Côte d'Opale, F-62200 Boulogne sur Mer, Univ. Lille, F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Odile Broux
- Marrow Adiposity and Bone Lab (MABLab) ULR4490, Université du Littoral Côte d'Opale, F-62200 Boulogne sur Mer, Univ. Lille, F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Paul Magneron
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France
| | - Felipe Prosper
- Hemato-Oncology Program. CIMA Universidad de Navarra-IdiSNA, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Hematology and Cell Therapy Department, Clinica Universidad de Navarra, IdiSNA, Pamplona, Spain; Cancer Center Universidad de Navarra (CCUN), Pamplona, Spain
| | - Christophe Chauveau
- Marrow Adiposity and Bone Lab (MABLab) ULR4490, Université du Littoral Côte d'Opale, F-62200 Boulogne sur Mer, Univ. Lille, F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Jessem Landoulsi
- Sorbonne Université, CNRS, Laboratoire de Réactivité de Surface, LRS, F-75005, Paris, France
| | - Francis Berenbaum
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France; Rheumatology Department, AP-HP Saint-Antoine Hospital, 184, Rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Juan R Rodriguez-Madoz
- Hemato-Oncology Program. CIMA Universidad de Navarra-IdiSNA, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Cancer Center Universidad de Navarra (CCUN), Pamplona, Spain
| | - Marie-Hélène Lafage-Proust
- Université de Lyon - Université Jean Monnet, INSERM U1059, Faculté de Médecine, F-42270 Saint-Priest en Jarez, France
| | - Stéphanie Lucas
- Marrow Adiposity and Bone Lab (MABLab) ULR4490, Université du Littoral Côte d'Opale, F-62200 Boulogne sur Mer, Univ. Lille, F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Xavier Houard
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France.
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9
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Liu H, Liu L, Rosen CJ. Bone Marrow Adipocytes as Novel Regulators of Metabolic Homeostasis: Clinical Consequences of Bone Marrow Adiposity. Curr Obes Rep 2025; 14:9. [PMID: 39808256 DOI: 10.1007/s13679-024-00594-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/21/2024] [Indexed: 01/16/2025]
Abstract
PURPOSE OF REVIEW Bone marrow adipose tissue is a distinctive fat depot located within the skeleton, with the potential to influence both local and systemic metabolic processes. Although significant strides have been made in understanding bone marrow adipose tissue over the past decade, many questions remain regarding their precise lineage and functional roles. RECENT FINDINGS Recent studies have highlighted bone marrow adipose tissue's involvement in continuous cross-talk with other organs and systems, exerting both endocrine and paracrine functions that play a crucial role in metabolic homeostasis, skeletal remodeling, hematopoiesis, and the progression of bone metastases. The advancement of imaging techniques, particularly cross-sectional imaging, has profoundly expanded our understanding of the complexities beyond the traditional view of bone marrow adipose tissue as an inert depot. Notably, marrow adipocytes are anatomically and functionally distinct from brown, beige, and classic white adipocytes. Emerging evidence suggests that bone marrow adipocytes, bone marrow adipose tissue originate from the differentiation of bone marrow mesenchymal stromal cells; however, they appear to be a heterogeneous population with varying metabolic profiles, lipid compositions, secretory properties, and functional responses depending on their specific location within the bone marrow. This review provides an up-to-date synthesis of current knowledge on bone marrow adipocytes, emphasizing the relationships between bone marrow adipogenesis and factors such as aging, osteoporosis, obesity, and bone marrow tumors or metastases, thereby elucidating the mechanisms underlying musculoskeletal pathophysiology.
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Affiliation(s)
- Hanghang Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology &, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
- Maine Medical Center Research Institute, Maine Medical Center, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Linyi Liu
- Maine Medical Center Research Institute, Maine Medical Center, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Clifford J Rosen
- Maine Medical Center Research Institute, Maine Medical Center, 81 Research Drive, Scarborough, ME, 04074, USA.
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Trivanović D, Vujačić M, Arsić A, Kukolj T, Rajković M, Bogosavljević N, Baščarević Z, Maljković Ružičić M, Kovačević J, Jauković A. Skeletal Site-Specific Lipid Profile and Hematopoietic Progenitors of Bone Marrow Adipose Tissue in Patients Undergoing Primary Hip Arthroplasty. Metabolites 2025; 15:16. [PMID: 39852359 PMCID: PMC11767117 DOI: 10.3390/metabo15010016] [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: 12/10/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/26/2025] Open
Abstract
BACKGROUND/OBJECTIVES Bone marrow adipose tissue (BMAT) has been described as an important biomechanic and lipotoxic factor with negative impacts on skeletal and hematopoietic system regeneration. BMAT undergoes metabolic and cellular adaptations with age and disease, being a source of potential biomarkers. However, there is no evidence on the lipid profile and cellularity at different skeletal locations in osteoarthritis patients undergoing primary hip arthroplasty. METHODS Acetabular and femoral bone marrow (BM) and gluteofemoral subcutaneous adipose tissue (gfSAT) were obtained from matched patients undergoing hip replacement surgery. BM, BMAT, and gfSAT were explored at the levels of total lipids, fatty acids, and cells by using thin-layerand gas chromatography, ex vivo cellular assays, and flow cytometry. RESULTS BMAT content was significantly higher in femoral than in acetabular BM. Total lipid analyses revealed significantly lower triglyceride content in femoral than in acetabular BMAT and gfSAT. Frequencies of saturated palmitic, myristic, and stearic acids were higher in femoral than in acetabular BMAT and gfSAT. The content of CD45+CD34+ cells within femoral BMAT was higher than in acetabular BMAT or gfSAT. This was associated with a higher incidence of total clonogenic hematopoietic progenitors and late erythroid colonies CFU-E in femoral BMAT when compared to acetabular BMAT, similar to their BM counterparts. CONCLUSIONS Collectively, our results indicate that the lipid profiles of hip bone and femoral BMAT impose significantly different microenvironments and distributions of cells with hematopoietic potential. These findings might bring forth new inputs for defining BMAT biology and setting novel directions in OA disease investigations.
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Affiliation(s)
- Drenka Trivanović
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (T.K.); (M.R.); (A.J.)
| | - Marko Vujačić
- Institute for Orthopedy Banjica, 11000 Belgrade, Serbia; (M.V.); (N.B.); (Z.B.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Aleksandra Arsić
- Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia;
| | - Tamara Kukolj
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (T.K.); (M.R.); (A.J.)
| | - Milica Rajković
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (T.K.); (M.R.); (A.J.)
| | - Nikola Bogosavljević
- Institute for Orthopedy Banjica, 11000 Belgrade, Serbia; (M.V.); (N.B.); (Z.B.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Zoran Baščarević
- Institute for Orthopedy Banjica, 11000 Belgrade, Serbia; (M.V.); (N.B.); (Z.B.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | | | - Jovana Kovačević
- Faculty of Mathematics, University of Belgrade, 11000 Belgrade, Serbia; (M.M.R.); (J.K.)
- Institute for Artificial Intelligence Research and Development of Serbia, 21000 Novi Sad, Serbia
| | - Aleksandra Jauković
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (T.K.); (M.R.); (A.J.)
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11
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Kisar Tunca S, Unal R. Adipocyte-derived fatty acid uptake induces obesity-related breast cancer progression: a review. Mol Biol Rep 2024; 52:39. [PMID: 39644365 DOI: 10.1007/s11033-024-10139-x] [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: 11/25/2024] [Indexed: 12/09/2024]
Abstract
Obesity is a metabolic disorder that occurs when excess energy taken into the body is stored as fat. It is known that this metabolic imbalance affects the development of other diseases such as cancer, cardiovascular diseases, insulin resistance, and diabetes. The main cellular component of adipose tissue is adipocytes, and the environmental interactions of adipocytes are important to study the mechanism of disorder formation. Breast tissue is rich in adipose tissue and obesity is known to be an important risk factor in the development of breast cancer. Altered adipogenesis and lipogenesis processes in adipocytes in breast tissue support tumor development through the transfer of fatty acids released from adipocytes. We believe that blending adipocyte biology with breast cancer development is important for investigating the mechanisms that regulate breast tumor malignant behavior and providing new targets for treatment. Fatty acids, which are an energy source for breast cancer cells, are discussed from molecular perspectives in this review.
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Affiliation(s)
- Selin Kisar Tunca
- Faculty of Science, Department of Molecular Biology and Genetics, Mugla Sitki Kocman University, Mugla, Turkey
| | - Resat Unal
- Faculty of Science, Department of Molecular Biology and Genetics, Mugla Sitki Kocman University, Mugla, Turkey.
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12
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Hosain O, Clinkenbeard EL. Adiposity and Mineral Balance in Chronic Kidney Disease. Curr Osteoporos Rep 2024; 22:561-575. [PMID: 39394545 DOI: 10.1007/s11914-024-00884-0] [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] [Accepted: 08/27/2024] [Indexed: 10/13/2024]
Abstract
PURPOSE OF REVIEW Bone homeostasis is balanced between formation and resorption activities and remain in relative equilibrium. Under disease states this process is disrupted, favoring more resorption over formation, leading to significant bone loss and fracture incidence. This aspect is a hallmark for patients with chronic kidney disease mineral and bone disorder (CKD-MBD) affecting a significant portion of the population, both in the United States and worldwide. Further study into the underlying effects of the uremic microenvironment within bone during CKD-MBD are critical as fracture incidence in this patient population not only leads to increased morbidity, but also increased mortality. Lack of bone homeostasis also leads to mineral imbalance contributing to cardiovascular calcifications. One area understudied is the possible involvement of bone marrow adipose tissue (BMAT) during the progression of CKD-MBD. RECENT FINDINGS BMAT accumulation is found during aging and in several disease states, some of which overlap as CKD etiologies. Importantly, research has found presence of BMAT inversely correlates with bone density and volume. Understanding the underlying molecular mechanisms for BMAT formation and accumulation during CKD-MBD may offer a potential therapeutic avenue to improve bone homeostasis and ultimately mineral metabolism.
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Affiliation(s)
- Ozair Hosain
- Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN, 46022, USA
- Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA
| | - Erica L Clinkenbeard
- Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA.
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13
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Deng S, Zhang S, Shen T, Wang X, Gao Z, Zhang W, Dai K, Wang J, Liu C. Amphiphilic cytokine traps remodel marrow adipose tissue for hematopoietic microenvironment amelioration. Bioact Mater 2024; 42:226-240. [PMID: 39285915 PMCID: PMC11404087 DOI: 10.1016/j.bioactmat.2024.08.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 09/19/2024] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is extensively employed in the treatment of hematological malignancies but is markedly constrained by the paucity of hematopoietic stem/progenitor cells (HSPCs). Recent studies have found that marrow adipose tissue (MAT) acts on hematopoiesis through complicated mechanisms. Therefore, the osteo-organoids fabricated in vivo using biomaterials loaded with recombinant human bone morphogenetic protein 2 (rhBMP-2) have been used as models of MAT for our research. To obtain sufficient amounts of therapeutic HSPCs and healthy MAT, we have developed amphiphilic chitosan (AC)-gelatin as carriers of rhBMP-2 to the regulate type conversion of adipose tissue and trap hematopoietic growth factors. Unlike medicine interventions or cell therapies, the traps based on AC not only attenuate the occupancy of adipocytes within the hematopoietic microenvironment while preserving stem cell factor concentrations, but also improve marrow metabolism by promoting MAT browning. In conclusion, this approach increases the proportion of HSPCs in osteo-organoids, and optimizes the composition and metabolic status of MAT. These findings furnish an experimental basis for regulating hematopoiesis in vivo through materials that promote the development of autologous HSPCs. Additionally, this approach presents a theoretical model of rapid adipogenesis for the study of adipose-related pathologies and potential pharmacological targets.
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Affiliation(s)
- Shunshu Deng
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, PR China
- Key Laboratory for Ultrafine Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Shuang Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Key Laboratory for Ultrafine Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Tong Shen
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Key Laboratory for Ultrafine Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Xuanlin Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Key Laboratory for Ultrafine Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Zehua Gao
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Key Laboratory for Ultrafine Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Wenchao Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Key Laboratory for Ultrafine Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Kai Dai
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Key Laboratory for Ultrafine Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Jing Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Changsheng Liu
- Key Laboratory for Ultrafine Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, PR China
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14
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Zapata-Linares N, Loisay L, de Haro D, Berenbaum F, Hügle T, Geurts J, Houard X. Systemic and joint adipose tissue lipids and their role in osteoarthritis. Biochimie 2024; 227:130-138. [PMID: 39343353 DOI: 10.1016/j.biochi.2024.09.015] [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: 04/19/2024] [Revised: 08/09/2024] [Accepted: 09/26/2024] [Indexed: 10/01/2024]
Abstract
Osteoarthritis (OA) is a major disease whose prevalence increases with aging, sedentary lifestyles, and obesity. The association between obesity and OA has been well documented, but the precise mechanisms underlying this heightened risk remain unclear. While obesity imposes greater forces on joints, systemic fat-derived factors such as lipids or adipokine may potentially act on the pathophysiology of OA, but the exact role of these factors in weight-bearing and non-weight-bearing joints remains elusive. Intra-articular adipose tissues (IAAT) have gained significant attention for actively participating in OA pathogenesis by interacting with various joint tissues. Lipid content has been proposed as a diagnostic target for early OA detection and a potential source of biomarkers. Moreover, targeting a specific IAAT called infrapatellar fat pad (IFP) and its lipids hold promise for attenuating OA-associated inflammation. Conversely, bone marrow adipose tissue (BMAT), which was long thought to be an inert filling tissue, is now increasingly considered a dynamic tissue whose volume and lipid content regulate bone remodeling in pathological conditions. Given OA's ability to alter adipose tissues, particularly those within the joint (IFP and BMAT), and the influence of adipose tissues on OA pathogenesis, this review examines the lipids produced by OA-associated adipose tissues, shedding light on their potential role in OA pathophysiology and highlighting them as potential therapeutic targets.
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Affiliation(s)
- Natalia Zapata-Linares
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), F-75012, Paris, France
| | - Léa Loisay
- Service of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Diego de Haro
- Service of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Francis Berenbaum
- Rheumatology Department, AP-HP Saint-Antoine Hospital, 184, rue du Faubourg Saint-Antoine, F-75012, Paris, France
| | - Thomas Hügle
- Service of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jeroen Geurts
- Service of Rheumatology, Department of Musculoskeletal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
| | - Xavier Houard
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), F-75012, Paris, France.
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15
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Briand-Mésange F, Gennero I, Salles J, Trudel S, Dahan L, Ausseil J, Payrastre B, Salles JP, Chap H. From Classical to Alternative Pathways of 2-Arachidonoylglycerol Synthesis: AlterAGs at the Crossroad of Endocannabinoid and Lysophospholipid Signaling. Molecules 2024; 29:3694. [PMID: 39125098 PMCID: PMC11314389 DOI: 10.3390/molecules29153694] [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: 06/21/2024] [Revised: 07/27/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cβ1 (PLCβ1) and diacylglycerol lipase α (DAGLα), contributing to retrograde signaling upon interaction with presynaptic CB1. However, 2-AG production might also involve various combinations of PLC and DAGL isoforms, as well as additional intracellular pathways implying other enzymes and substrates. Three other alternative pathways of 2-AG synthesis rest on the extracellular cleavage of 2-arachidonoyl-lysophospholipids by three different hydrolases: glycerophosphodiesterase 3 (GDE3), lipid phosphate phosphatases (LPPs), and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6-7). We propose the names of AlterAG-1, -2, and -3 for three pathways sharing an ectocellular localization, allowing them to convert extracellular lysophospholipid mediators into 2-AG, thus inducing typical signaling switches between various G-protein-coupled receptors (GPCRs). This implies the critical importance of the regioisomerism of both lysophospholipid (LPLs) and 2-AG, which is the object of deep analysis within this review. The precise functional roles of AlterAGs are still poorly understood and will require gene invalidation approaches, knowing that both 2-AG and its related lysophospholipids are involved in numerous aspects of physiology and pathology, including cancer, inflammation, immune defenses, obesity, bone development, neurodegeneration, or psychiatric disorders.
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Affiliation(s)
- Fabienne Briand-Mésange
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
| | - Isabelle Gennero
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Service de Biochimie, Institut Fédératif de Biologie, 31059 Toulouse, France
| | - Juliette Salles
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Service de Psychiatrie D’urgences, de Crise et de Liaison, Institut des Handicaps Neurologiques, Psychiatriques et Sensoriels, 31059 Toulouse, France
| | - Stéphanie Trudel
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Service de Biochimie, Institut Fédératif de Biologie, 31059 Toulouse, France
| | - Lionel Dahan
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France;
| | - Jérôme Ausseil
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Service de Biochimie, Institut Fédératif de Biologie, 31059 Toulouse, France
| | - Bernard Payrastre
- I2MC-Institute of Metabolic and Cardiovascular Diseases, INSERM UMR1297 and University of Toulouse III, 31400 Toulouse, France;
- Centre Hospitalier Universitaire de Toulouse, Laboratoire d’Hématologie, 31400 Toulouse, France
| | - Jean-Pierre Salles
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Unité d’Endocrinologie et Maladies Osseuses, Hôpital des Enfants, 31059 Toulouse, France
| | - Hugues Chap
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Académie des Sciences, Inscriptions et Belles Lettres de Toulouse, Hôtel d’Assézat, 31000 Toulouse, France
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16
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Trivanović D, Vujačić M, Labella R, Djordjević IO, Ćazić M, Chernak B, Jauković A. Molecular Deconvolution of Bone Marrow Adipose Tissue Interactions with Malignant Hematopoiesis: Potential for New Therapy Development. Curr Osteoporos Rep 2024; 22:367-377. [PMID: 38922359 DOI: 10.1007/s11914-024-00879-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2024] [Indexed: 06/27/2024]
Abstract
PURPOSE OF REVIEW Along with a strong impact on skeletal integrity, bone marrow adipose tissue (BMAT) is an important modulator of the adult hematopoietic system. This review will summarize the current knowledge on the causal relationship between bone marrow (BM) adipogenesis and the development and progression of hematologic malignancies. RECENT FINDINGS BM adipocytes (BMAds) support a number of processes promoting oncogenesis, including the evolution of clonal hematopoiesis, malignant cell survival, proliferation, angiogenesis, and chemoresistance. In addition, leukemic cells manipulate surrounding BMAds by promoting lipolysis and release of free fatty acids, which are then utilized by leukemic cells via β-oxidation. Therefore, limiting BM adipogenesis, blocking BMAd-derived adipokines, or lipid metabolism obstruction have been considered as potential treatment options for hematological malignancies. Leukemic stem cells rely heavily on BMAds within the structural BM microenvironment for necessary signals which foster disease progression. Further development of 3D constructs resembling BMAT at different skeletal regions are critical to better understand these relationships in geometric space and may provide essential insight into the development of hematologic malignancies within the BM niche. In turn, these mechanisms provide promising potential as novel approaches to targeting the microenvironment with new therapeutic strategies.
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Affiliation(s)
- Drenka Trivanović
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000, Belgrade, Serbia.
| | - Marko Vujačić
- Institute for Orthopedy Banjica, 11000, Belgrade, Serbia
- School of Medicine, University of Belgrade, 11000, Belgrade, Serbia
| | - Rossella Labella
- Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA
- Edward P. Evans Center for Myelodysplastic Syndromes, Columbia University Medical Center, New York, NY, USA
| | - Ivana Okić Djordjević
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000, Belgrade, Serbia
| | - Marija Ćazić
- Department of Hematology and Oncology, University Children's Hospital Tiršova, 11000, Belgrade, Serbia
| | - Brian Chernak
- Division of Hematology/Oncology, Columbia University, New York, NY, USA
| | - Aleksandra Jauković
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000, Belgrade, Serbia
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17
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Froemming MN, Khosla S, Farr JN. Marrow Adipocyte Senescence in the Pathogenesis of Bone Loss. Curr Osteoporos Rep 2024; 22:378-386. [PMID: 38829487 PMCID: PMC11913023 DOI: 10.1007/s11914-024-00875-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/23/2024] [Indexed: 06/05/2024]
Abstract
PURPOSE OF REVIEW Beyond aging, senescent cells accumulate during multiple pathological conditions, including chemotherapy, radiation, glucocorticoids, obesity, and diabetes, even earlier in life. Therefore, cellular senescence represents a unifying pathogenic mechanism driving skeletal and metabolic disorders. However, whether senescent bone marrow adipocytes (BMAds) are causal in mediating skeletal dysfunction has only recently been evaluated. RECENT FINDINGS Despite evidence of BMAd senescence following glucocorticoid therapy, additional evidence for BMAd senescence in other conditions has thus far been limited. Because the study of BMAds presents unique challenges making these cells difficult to isolate and image, here we review issues and approaches to overcome such challenges, and present advancements in isolation and histological techniques that may help with the future study of senescent BMAds. Further insights into the roles of BMAd senescence in the pathogenesis of skeletal dysfunction may have important basic science and clinical implications for human physiology and disease.
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Affiliation(s)
- Mitchell N Froemming
- Division of Endocrinology, Rochester, MN, 55905, USA
- Robert and Arlene Kogod Center On Aging, Rochester, MN, 55905, USA
| | - Sundeep Khosla
- Division of Endocrinology, Rochester, MN, 55905, USA
- Robert and Arlene Kogod Center On Aging, Rochester, MN, 55905, USA
| | - Joshua N Farr
- Division of Endocrinology, Rochester, MN, 55905, USA.
- Robert and Arlene Kogod Center On Aging, Rochester, MN, 55905, USA.
- Division of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
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Zhang X, Majumdar A, Kim C, Kleiboeker B, Magee KL, Learman BS, Thomas SA, Lodhi IJ, MacDougald OA, Scheller EL. Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.30.605812. [PMID: 39131323 PMCID: PMC11312544 DOI: 10.1101/2024.07.30.605812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Several adipose depots, including constitutive bone marrow adipose tissue (cBMAT), resist conventional lipolytic cues, making them metabolically non-responsive. However, under starvation, wasting, or cachexia, the body can eventually catabolize these stable adipocytes through unknown mechanisms. To study this, we developed a mouse model of brain-evoked depletion of all fat, including cBMAT, independent of food intake. Genetic, surgical, and chemical approaches demonstrated that depletion of stable fat required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system, and catecholamines. Instead, concurrent hypoglycemia and hypoinsulinemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors Acvr1c, G0s2, and Npr3. This was also sufficient to delipidate classical adipose depots. Overall, this work defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent in vivo neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.
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Affiliation(s)
- Xiao Zhang
- Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
| | - Anurag Majumdar
- Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA
| | - Clara Kim
- Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA
| | - Brian Kleiboeker
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Kristann L Magee
- Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA
| | - Brian S Learman
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Steven A Thomas
- Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA
| | - Irfan J Lodhi
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Ormond A MacDougald
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Erica L Scheller
- Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
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19
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Levi J, Guglielmetti C, Henrich TJ, Yoon JC, Gokhale PC, Reardon DA, Packiasamy J, Huynh L, Cabrera H, Ruzevich M, Blecha J, Peluso MJ, Huynh TL, An SM, Dornan M, Belanger AP, Nguyen QD, Seo Y, Song H, Chaumeil MM, VanBrocklin HF, Chae HD. [ 18F]F-AraG imaging reveals association between neuroinflammation and brown- and bone marrow adipose tissue. Commun Biol 2024; 7:793. [PMID: 38951146 PMCID: PMC11217368 DOI: 10.1038/s42003-024-06494-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 06/22/2024] [Indexed: 07/03/2024] Open
Abstract
Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.
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Affiliation(s)
- Jelena Levi
- CellSight Technologies Incorporated, San Francisco, CA, USA.
| | - Caroline Guglielmetti
- Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, USA
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
- Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, USA
| | - Timothy J Henrich
- Division of Experimental Medicine, University of California San Francisco, San Francisco, CA, USA
| | - John C Yoon
- Division of Endocrinology, Department of Internal Medicine, University of California Davis School of Medicine, Davis, CA, USA
| | | | | | | | - Lyna Huynh
- CellSight Technologies Incorporated, San Francisco, CA, USA
| | - Hilda Cabrera
- CellSight Technologies Incorporated, San Francisco, CA, USA
| | | | - Joseph Blecha
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - Michael J Peluso
- Division of HIV, ID and Global Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Tony L Huynh
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - Sung-Min An
- Division of Endocrinology, Department of Internal Medicine, University of California Davis School of Medicine, Davis, CA, USA
| | - Mark Dornan
- Molecular Cancer Imaging Facility, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Anthony P Belanger
- Molecular Cancer Imaging Facility, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Quang-Dé Nguyen
- Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Youngho Seo
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - Hong Song
- Department of Radiology, Stanford University, Palo Alto, CA, USA
| | - Myriam M Chaumeil
- Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, USA
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - Henry F VanBrocklin
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - Hee-Don Chae
- CellSight Technologies Incorporated, San Francisco, CA, USA
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20
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Wang L, Liu Y, Li K, Zhang W, Yuan Y, Ma K, Zhou F, Cheng Z, Geng J, Su Y, Guo Z, Blake GM, Cheng X, Liu Y, Engelke K, Vlug AG. Age and BMI have different effects on subcutaneous, visceral, liver, bone marrow, and muscle adiposity, as measured by CT and MRI. Obesity (Silver Spring) 2024; 32:1339-1348. [PMID: 38783517 DOI: 10.1002/oby.24040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 03/15/2024] [Accepted: 03/19/2024] [Indexed: 05/25/2024]
Abstract
OBJECTIVE We analyzed quantitative computed tomography (CT) and chemical shift-encoded magnetic resonance imaging (MRI) data from a Chinese cohort to investigate the effects of BMI and aging on different adipose tissue (AT) depots. METHODS In 400 healthy, community-dwelling individuals aged 22 to 83 years, we used MRI to quantify proton density fat fraction (PDFF) of the lumbar spine (L2-L4) bone marrow AT (BMAT), the psoas major and erector spinae (ES) muscles, and the liver. Abdominal total AT, visceral AT (VAT), and subcutaneous AT (SAT) areas were measured at the L2-L3 level using quantitative CT. Partial correlation analysis was used to evaluate the relationship of each AT variable with age and BMI. Multiple linear regression analysis was performed in which each AT variable was evaluated in turn as a function of age and the other five independent AT measurements. RESULTS Of the 168 men, 29% had normal BMI (<24.0 kg/m2), 47% had overweight (24.0-27.9 kg/m2), and 24% had obesity (≥ 28.0 kg/m2). In the 232 women, the percentages were 46%, 32%, and 22%, respectively. Strong or very strong correlations with BMI were found for total AT, VAT, and SAT in both sexes. BMAT and ES PDFF was strongly correlated with age in women and moderately correlated in men. In both sexes, BMAT PDFF correlated only with age and not with any of the other AT depots. Psoas PDFF correlated only with ES PDFF and not with age or the other AT depots. Liver PDFF correlated with BMI and VAT and weakly with SAT in men. VAT and SAT correlated with age and each other in both sexes. CONCLUSIONS Age and BMI are both associated with adiposity, but their effects differ depending on the type of AT.
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Affiliation(s)
- Ling Wang
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
- JST Sarcopenia Research Centre, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Yandong Liu
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Kai Li
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Wenshuang Zhang
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Yi Yuan
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Kangkang Ma
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Fengyun Zhou
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Zitong Cheng
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Jian Geng
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Yongbin Su
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Zhe Guo
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Glen M Blake
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Xiaoguang Cheng
- Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Yajun Liu
- JST Sarcopenia Research Centre, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
- Department of Spine Surgery, Beijing Jishuitan Hospital, Capital Medical University, National Center for Orthopaedics, Beijing, China
| | - Klaus Engelke
- Institute of Medical Physics, University Erlangen-Nuremberg, Nuremberg, Germany
- Department of Medicine 3 - Rheumatology and Immunology, FAU University of Erlangen-Nuremberg and University Hospital Erlangen, Erlangen, Germany
| | - Annegreet G Vlug
- Center for Bone Quality, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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21
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Zhang X, Tian L, Majumdar A, Scheller EL. Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations. Compr Physiol 2024; 14:5521-5579. [PMID: 39109972 PMCID: PMC11725182 DOI: 10.1002/cphy.c230016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic-rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521-5579, 2024.
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Affiliation(s)
- Xiao Zhang
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Linda Tian
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Anurag Majumdar
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Erica L. Scheller
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
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22
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Zapata-Linares N, Berenbaum F, Houard X. Role of joint adipose tissues in osteoarthritis. ANNALES D'ENDOCRINOLOGIE 2024; 85:214-219. [PMID: 38871517 DOI: 10.1016/j.ando.2024.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Osteoarthritis (OA) is the most common musculoskeletal disease, without any curative treatment. Obesity being the main modifiable risk factor for OA, much attention focused on the role of adipose tissues (AT). In addition to the involvement of visceral and subcutaneous AT via systemic ways, many arguments also highlight the involvement of local AT, present in joint tissues. Local AT include intra-articular AT (IAAT), which border the synovium, and bone marrow AT (BMAT) localized within marrow cavities in the bones. This review describes the known features and involvement of IAAT and BMAT in joint homeostasis and OA. Recent findings evidence that alteration in magnetic resonance imaging signal intensity of infrapatellar fat pad can be predictive of the development and progression of knee OA. IAAT and synovium are partners of the same functional unit; IAAT playing an early and pivotal role in synovial inflammation and fibrosis and OA pain. BMAT, whose functions have only recently begun to be studied, is in close functional interaction with its microenvironment. The volume and molecular profile of BMAT change according to the pathophysiological context, enabling fine regulation of haematopoiesis and bone metabolism. Although its role in OA has not yet been studied, the localization of BMAT, its functions and the importance of the bone remodelling processes that occur in OA argue in favour of a role for BMAT in OA.
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Affiliation(s)
- Natalia Zapata-Linares
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France
| | - Francis Berenbaum
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France; Rheumatology Department, AP-HP Saint-Antoine Hospital, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Xavier Houard
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France.
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23
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Abstract
Cells of the mammalian innate immune system have evolved to protect the host from various environmental or internal insults and injuries which perturb the homeostatic state of the organism. Among the lymphocytes of the innate immune system are natural killer (NK) cells, which circulate and survey host tissues for signs of stress, including infection or transformation. NK cells rapidly eliminate damaged cells in the blood or within tissues through secretion of cytolytic machinery and production of proinflammatory cytokines. To perform these effector functions while traversing between the blood and tissues, patrolling NK cells require sufficient fuel to meet their energetic demands. Here, we highlight the ability of NK cells to metabolically adapt across tissues, during times of nutrient deprivation and within tumor microenvironments. Whether at steady state, or during viral infection and cancer, NK cells readily shift their nutrient uptake and usage in order to maintain metabolism, survival, and function.
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Affiliation(s)
- Rebecca B. Delconte
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Joseph C. Sun
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA
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24
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Kumar V, Stewart JH. Obesity, bone marrow adiposity, and leukemia: Time to act. Obes Rev 2024; 25:e13674. [PMID: 38092420 DOI: 10.1111/obr.13674] [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: 09/21/2022] [Revised: 10/07/2023] [Accepted: 11/13/2023] [Indexed: 02/28/2024]
Abstract
Obesity has taken the face of a pandemic with less direct concern among the general population and scientific community. However, obesity is considered a low-grade systemic inflammation that impacts multiple organs. Chronic inflammation is also associated with different solid and blood cancers. In addition, emerging evidence demonstrates that individuals with obesity are at higher risk of developing blood cancers and have poorer clinical outcomes than individuals in a normal weight range. The bone marrow is critical for hematopoiesis, lymphopoiesis, and myelopoiesis. Therefore, it is vital to understand the mechanisms by which obesity-associated changes in BM adiposity impact leukemia development. BM adipocytes are critical to maintain homeostasis via different means, including immune regulation. However, obesity increases BM adiposity and creates a pro-inflammatory environment to upregulate clonal hematopoiesis and a leukemia-supportive environment. Obesity further alters lymphopoiesis and myelopoiesis via different mechanisms, which dysregulate myeloid and lymphoid immune cell functions mentioned in the text under different sequentially discussed sections. The altered immune cell function during obesity alters hematological malignancies and leukemia susceptibility. Therefore, obesity-induced altered BM adiposity, immune cell generation, and function impact an individual's predisposition and severity of leukemia, which should be considered a critical factor in leukemia patients.
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Affiliation(s)
- Vijay Kumar
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - John H Stewart
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Morehouse School of Medicine, Atlanta, Georgia, USA
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25
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Porro G, Sarkis R, Obergozo C, Godot L, Amato F, Humbert M, Naveiras O, Guiducci C. MarrowCellDLD: a microfluidic method for label-free retrieval of fragile bone marrow-derived cells. Sci Rep 2023; 13:22462. [PMID: 38105340 PMCID: PMC10725893 DOI: 10.1038/s41598-023-47978-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/20/2023] [Indexed: 12/19/2023] Open
Abstract
Functional bone marrow studies have focused primarily on hematopoietic progenitors, leaving limited knowledge about other fragile populations, such as bone marrow adipocytes (BMAds) and megakaryocytes. The isolation of these cells is challenging due to rupture susceptibility and large size. We introduce here a label-free cytometry microsystem, MarrowCellDLD, based on deterministic lateral displacement. MarrowCellDLD enables the isolation of large, fragile BM-derived cells based on intrinsic size properties while preserving their viability and functionality. Bone marrow adipocytes, obtained from mouse and human stromal line differentiation, as well as megakaryocytes, from primary human CD34+ hematopoietic stem and progenitor cells, were used for validation. Precise micrometer-range separation cutoffs were adapted for each cell type. Cells were sorted directly in culture media, without pre-labeling steps, and with real-time imaging for quality control. At least 106 cells were retrieved intact per sorting round. Our method outperformed two FACS instruments in purity and yield, particularly for large cell size fractions. MarrowCellDLD represents a non-destructive sorting tool for large, fragile BM-derived cells, facilitating the separation of pure populations of BMAds and megakaryocytes to further investigate their physiological and pathological roles.
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Affiliation(s)
- Gloria Porro
- Laboratory of Life Sciences Electronics, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
| | - Rita Sarkis
- Laboratory of Regenerative Hematopoiesis, Université de Lausanne (UNIL), Lausanne, Switzerland.
| | - Clara Obergozo
- Laboratory of Life Sciences Electronics, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Laboratory of Regenerative Hematopoiesis, Université de Lausanne (UNIL), Lausanne, Switzerland
| | - Lucie Godot
- Laboratory of Life Sciences Electronics, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Laboratory of Regenerative Hematopoiesis, Université de Lausanne (UNIL), Lausanne, Switzerland
| | - Francesco Amato
- Laboratory of Life Sciences Electronics, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Laboratory of Regenerative Hematopoiesis, Université de Lausanne (UNIL), Lausanne, Switzerland
| | - Magali Humbert
- Laboratory of Regenerative Hematopoiesis, Université de Lausanne (UNIL), Lausanne, Switzerland
| | - Olaia Naveiras
- Laboratory of Regenerative Hematopoiesis, Université de Lausanne (UNIL), Lausanne, Switzerland.
- Hematology Service, Departments of Oncology and Laboratory Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
| | - Carlotta Guiducci
- Laboratory of Life Sciences Electronics, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
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26
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Widjaja N, Jalava N, Chen Y, Ivaska KK. Perilipin-1 immunostaining improves semi-automated digital quantitation of bone marrow adipocytes in histological bone sections. Adipocyte 2023; 12:2252711. [PMID: 37649225 PMCID: PMC10472850 DOI: 10.1080/21623945.2023.2252711] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 08/16/2023] [Accepted: 08/16/2023] [Indexed: 09/01/2023] Open
Abstract
Bone marrow adipocytes (BMAds) are not just passive fillers inside the bone marrow compartment but respond to various metabolic changes. Assessment of those responses requires evaluation of the number of BMAds and their morphology for which laborious and error-prone manual histological analysis remains the most widely used method. Here, we report an alternative image analysis strategy to semi-automatically quantitate and analyse the morphology of BMAds in histological bone sections. Decalcified, formalin-fixed paraffin-embedded histological sections of long bones of Sprague-Dawley rats were stained with either haematoxylin and eosin (HE) or by immunofluorescent staining for adipocyte-specific protein perilipin-1 (PLIN1). ImageJ-based commands were constructed to detect BMAds sized 200 µm2 or larger from standardized 1 mm2 analysis regions by either classifying the background colour (HE) or the positive and circular PLIN1 fluorescent signal. Semi-automated quantitation strongly correlated with independent, single-blinded manual counts regardless of the staining method (HE-based: r=0.85, p<0.001; PLIN1 based: r=0.95, p<0.001). The detection error was higher in HE-stained sections than in PLIN1-stained sections (14% versus 5%, respectively; p<0.001), which was due to false-positive detections of unstained adipocyte-like circular structures. In our dataset, the total adiposity area from standardised ROIs in PLIN-1-stained sections correlated with that in whole-bone sections (r=0.60, p=0.02).
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Affiliation(s)
- Nicko Widjaja
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Niki Jalava
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Yimeng Chen
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Kaisa K. Ivaska
- Institute of Biomedicine, University of Turku, Turku, Finland
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27
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Diedrich JD, Cole CE, Pianko MJ, Colacino JA, Bernard JJ. Non-Toxicological Role of Aryl Hydrocarbon Receptor in Obesity-Associated Multiple Myeloma Cell Growth and Survival. Cancers (Basel) 2023; 15:5255. [PMID: 37958428 PMCID: PMC10649826 DOI: 10.3390/cancers15215255] [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: 09/12/2023] [Revised: 10/27/2023] [Accepted: 10/29/2023] [Indexed: 11/15/2023] Open
Abstract
Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors-monoclonal gammopathy of undetermined significance-and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to facilitate MM cell growth via secreted factors, but the nature of these secreted factors and their mechanism of action have not been fully elucidated. The elevated expression of aryl hydrocarbon receptor (AhR) is associated with a variety of different cancers, including MM; however, the role of AhR activity in obesity-associated MM cell growth and survival has not been explored. Indeed, this is of particular interest as it has been recently shown that bone marrow adipocytes are a source of endogenous AhR ligands. Using multiple in vitro models of tumor-adipocyte crosstalk to mimic the bone microenvironment, we identified a novel, non-toxicological role of the adipocyte-secreted factors in the suppression of AhR activity in MM cells. A panel of six MM cell lines were cultured in the presence of bone marrow adipocytes in (1) a direct co-culture, (2) a transwell co-culture, or (3) an adipocyte-conditioned media to interrogate the effects of the secreted factors on MM cell AhR activity. Nuclear localization and the transcriptional activity of the AhR, as measured by CYP1A1 and CYP1B1 gene induction, were suppressed by exposure to BMA-derived factors. Additionally, decreased AhR target gene expression was associated with worse clinical outcomes. The knockdown of AhR resulted in reduced CYP1B1 expression and increased cellular growth. This tumor-suppressing role of CYP1A1 and CYP1B1 was supported by patient data which demonstrated an association between reduced target gene expression and worse overall survival. These data demonstrated a novel mechanism by which bone marrow adipocytes promote MM progression.
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Affiliation(s)
- Jonathan D. Diedrich
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA;
| | - Craig E. Cole
- Department of Medicine, Division of Hematology/Oncology, Michigan State University, East Lansing, MI 48910, USA;
- Karmanos Cancer Institute, McLaren Greater Lansing, Lansing, MI 48910, USA
- Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Matthew J. Pianko
- Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Justin A. Colacino
- Department of Nutritional Sciences, University of Michigan, Ann Arbor, MI 48109, USA;
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jamie J. Bernard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA;
- Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
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Moein S, Ahmadbeigi N, Adibi R, Kamali S, Moradzadeh K, Nematollahi P, Nardi NB, Gheisari Y. Regenerative potential of multinucleated cells: bone marrow adiponectin-positive multinucleated cells take the lead. Stem Cell Res Ther 2023; 14:173. [PMID: 37403181 DOI: 10.1186/s13287-023-03400-w] [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: 08/08/2022] [Accepted: 06/13/2023] [Indexed: 07/06/2023] Open
Abstract
BACKGROUND Polyploid cells can be found in a wide evolutionary spectrum of organisms. These cells are assumed to be involved in tissue regeneration and resistance to stressors. Although the appearance of large multinucleated cells (LMCs) in long-term culture of bone marrow (BM) mesenchymal cells has been reported, the presence and characteristics of such cells in native BM and their putative role in BM reconstitution following injury have not been fully investigated. METHODS BM-derived LMCs were explored by time-lapse microscopy from the first hours post-isolation to assess their colony formation and plasticity. In addition, sub-lethally irradiated mice were killed every other day for four weeks to investigate the histopathological processes during BM regeneration. Moreover, LMCs from GFP transgenic mice were transplanted to BM-ablated recipients to evaluate their contribution to tissue reconstruction. RESULTS BM-isolated LMCs produced mononucleated cells with characteristics of mesenchymal stromal cells. Time-series inspections of BM sections following irradiation revealed that LMCs are highly resistant to injury and originate mononucleated cells which reconstitute the tissue. The regeneration process was synchronized with a transient augmentation of adipocytes suggesting their contribution to tissue repair. Additionally, LMCs were found to be adiponectin positive linking the observations on multinucleation and adipogenesis to BM regeneration. Notably, transplantation of LMCs to myeloablated recipients could reconstitute both the hematopoietic system and BM stroma. CONCLUSIONS A population of resistant multinucleated cells reside in the BM that serves as the common origin of stromal and hematopoietic lineages with a key role in tissue regeneration. Furthermore, this study underscores the contribution of adipocytes in BM reconstruction.
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Affiliation(s)
- Shiva Moein
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Naser Ahmadbeigi
- Gene Therapy Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Rezvan Adibi
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sara Kamali
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran
| | - Kobra Moradzadeh
- Gene Therapy Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Pardis Nematollahi
- Department of Pathology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nance Beyer Nardi
- Institute of Cardiology of Rio Grande do Sul, Av Princesa Isabel 370, Porto Alegre, RS, 90620-001, Brazil
| | - Yousof Gheisari
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran.
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Reiche ME, Poels K, Bosmans LA, Vos WG, Van Tiel CM, Gijbels MJJ, Aarts SABM, Den Toom M, Beckers L, Weber C, Atzler D, Rensen PCN, Kooijman S, Lutgens E. Adipocytes control hematopoiesis and inflammation through CD40 signaling. Haematologica 2023; 108:1873-1885. [PMID: 36475519 PMCID: PMC10316249 DOI: 10.3324/haematol.2022.281482] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 11/30/2022] [Indexed: 08/18/2024] Open
Abstract
The co-stimulatory CD40-CD40L dyad plays an important role in chronic inflammatory diseases associated with aging. Although CD40 is mainly expressed by immune cells, CD40 is also present on adipocytes. We aimed to delineate the role of adipocyte CD40 in the aging hematopoietic system and evaluated the effects of adipocyte CD40 deficiency on cardiometabolic diseases. Adult adipocyte CD40-deficient mice (AdiCD40KO) mice had a decrease in bone marrow hematopoietic stem cells (Lin-Sca+cKit+, LSK) and common lymphoid progenitors, which was associated with increased bone marrow adiposity and T-cell activation, along with elevated plasma corticosterone levels, a phenotype that became more pronounced with age. Atherosclerotic AdiCD40koApoE-/- (CD40AKO) mice also displayed changes in the LSK population, showing increased myeloid and lymphoid multipotent progenitors, and augmented corticosterone levels. Increased T-cell activation could be observed in bone marrow, spleen, and adipose tissue, while the numbers of B cells were decreased. Although atherosclerosis was reduced in CD40AKO mice, plaques contained more activated T cells and larger necrotic cores. Analysis of peripheral adipose tissue in a diet-induced model of obesity revealed that obese AdiCD40KO mice had increased T-cell activation in adipose tissue and lymphoid organs, but decreased weight gain and improved insulin sensitivity, along with increased fat oxidation. In conclusion, adipocyte CD40 plays an important role in maintaining immune cell homeostasis in bone marrow during aging and chronic inflammatory diseases, particularly of the lymphoid populations. Although adipocyte CD40 deficiency reduces atherosclerosis burden and ameliorates diet-induced obesity, the accompanying T-cell activation may eventually aggravate cardiometabolic diseases.
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Affiliation(s)
- Myrthe E Reiche
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands; Department of Medical Cell Biology, Uppsala University, Uppsala
| | - Kikkie Poels
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Laura A Bosmans
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Winnie G Vos
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Claudia M Van Tiel
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Marion J J Gijbels
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Department of Biochemistry, Maastricht University, Maastricht
| | - Suzanne A B M Aarts
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Myrthe Den Toom
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Linda Beckers
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam
| | - Christian Weber
- Cardiovascular Research Institute Maastricht (CARIM), Department of Biochemistry, Maastricht University, Maastricht, The Netherlands; Institute of Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, Munich, Germany; German Centre of Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich
| | - Dorothee Atzler
- Institute of Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, Munich, Germany; German Centre of Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität, Munich
| | - Patrick C N Rensen
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden
| | - Sander Kooijman
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden
| | - Esther Lutgens
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands; Institute of Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, Munich, Germany; German Centre of Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Cardiovascular Medicine, Experimental CardioVascular Immunology Laboratory, Mayo Clinic, Rochester, MN.
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30
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Pottosin I, Olivas-Aguirre M, Dobrovinskaya O. In vitro simulation of the acute lymphoblastic leukemia niche: a critical view on the optimal approximation for drug testing. J Leukoc Biol 2023; 114:21-41. [PMID: 37039524 DOI: 10.1093/jleuko/qiad039] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 03/29/2023] [Accepted: 03/31/2023] [Indexed: 04/12/2023] Open
Abstract
Acute lymphoblastic leukemia with the worst prognosis is related to minimal residual disease. Minimal residual disease not only depends on the individual peculiarities of leukemic clones but also reflects the protective role of the acute lymphoblastic leukemia microenvironment. In this review, we discuss in detail cell-to-cell interactions in the 2 leukemic niches, more explored bone marrow and less studied extramedullary adipose tissue. A special emphasis is given to multiple ways of interactions of acute lymphoblastic leukemia cells with the bone marrow or extramedullary adipose tissue microenvironment, indicating observed differences in B- and T-cell-derived acute lymphoblastic leukemia behavior. This analysis argued for the usage of coculture systems for drug testing. Starting with a review of available sources and characteristics of acute lymphoblastic leukemia cells, mesenchymal stromal cells, endothelial cells, and adipocytes, we have then made an update of the available 2-dimensional and 3-dimensional systems, which bring together cellular elements, components of the extracellular matrix, or its imitation. We discussed the most complex available 3-dimensional systems like "leukemia-on-a-chip," which include either a prefabricated microfluidics platform or, alternatively, the microarchitecture, designed by using the 3-dimensional bioprinting technologies. From our analysis, it follows that for preclinical antileukemic drug testing, in most cases, intermediately complex in vitro cell systems are optimal, such as a "2.5-dimensional" coculture of acute lymphoblastic leukemia cells with niche cells (mesenchymal stromal cells, endothelial cells) plus matrix components or scaffold-free mesenchymal stromal cell organoids, populated by acute lymphoblastic leukemia cells. Due to emerging evidence for the correlation of obesity and poor prognosis, a coculture of adipocytes with acute lymphoblastic leukemia cells as a drug testing system is gaining shape.
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Affiliation(s)
- Igor Pottosin
- Laboratory of Immunobiology and Ionic Transport Regulation, University Center for Biomedical Research, University of Colima, Av. Enrique Arreola Silva 883, Guzmán City, Jalisco, 49000, Mexico
| | - Miguel Olivas-Aguirre
- Laboratory of Immunobiology and Ionic Transport Regulation, University Center for Biomedical Research, University of Colima, Av. Enrique Arreola Silva 883, Guzmán City, Jalisco, 49000, Mexico
- Division of Exact, Natural and Technological Sciences, South University Center (CUSUR), University of Guadalajara, Jalisco, Mexico
| | - Oxana Dobrovinskaya
- Laboratory of Immunobiology and Ionic Transport Regulation, University Center for Biomedical Research, University of Colima, Av. Enrique Arreola Silva 883, Guzmán City, Jalisco, 49000, Mexico
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Austin MJ, Kalampalika F, Cawthorn WP, Patel B. Turning the spotlight on bone marrow adipocytes in haematological malignancy and non-malignant conditions. Br J Haematol 2023; 201:605-619. [PMID: 37067783 PMCID: PMC10952811 DOI: 10.1111/bjh.18748] [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: 12/20/2022] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 04/18/2023]
Abstract
Whilst bone marrow adipocytes (BMAd) have long been appreciated by clinical haemato-pathologists, it is only relatively recently, in the face of emerging data, that the adipocytic niche has come under the watchful eye of biologists. There is now mounting evidence to suggest that BMAds are not just a simple structural entity of bone marrow microenvironments but a bona fide driver of physio- and pathophysiological processes relevant to multiple aspects of health and disease. Whilst the truly multifaceted nature of BMAds has only just begun to emerge, paradigms have shifted already for normal, malignant and non-malignant haemopoiesis incorporating a view of adipocyte regulation. Major efforts are ongoing, to delineate the routes by which BMAds participate in health and disease with a final aim of achieving clinical tractability. This review summarises the emerging role of BMAds across the spectrum of normal and pathological haematological conditions with a particular focus on its impact on cancer therapy.
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Affiliation(s)
- Michael J. Austin
- Barts Cancer Institute, Centre for Haemato‐OncologyQueen Mary University of LondonLondonUK
| | - Foteini Kalampalika
- Barts Cancer Institute, Centre for Haemato‐OncologyQueen Mary University of LondonLondonUK
| | - William P. Cawthorn
- BHF/University Centre for Cardiovascular Science, Edinburgh BioquarterUniversity of EdinburghEdinburghUK
| | - Bela Patel
- Barts Cancer Institute, Centre for Haemato‐OncologyQueen Mary University of LondonLondonUK
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32
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Liu L, Rosen CJ. New Insights into Calorie Restriction Induced Bone Loss. Endocrinol Metab (Seoul) 2023; 38:203-213. [PMID: 37150516 PMCID: PMC10164494 DOI: 10.3803/enm.2023.1673] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 03/30/2023] [Indexed: 05/09/2023] Open
Abstract
Caloric restriction (CR) is now a popular lifestyle choice due to its ability in experimental animals to improve lifespan, reduce body weight, and lessen oxidative stress. However, more and more emerging evidence suggests this treatment requires careful consideration because of its detrimental effects on the skeletal system. Experimental and clinical studies show that CR can suppress bone growth and raise the risk of fracture, but the specific mechanisms are poorly understood. Reduced mechanical loading has long been thought to be the primary cause of weight loss-induced bone loss from calorie restriction. Despite fat loss in peripheral depots with calorie restriction, bone marrow adipose tissue (BMAT) increases, and this may play a significant role in this pathological process. Here, we update recent advances in our understanding of the effects of CR on the skeleton, the possible pathogenic role of BMAT in CR-induced bone loss, and some strategies to mitigate any potential side effects on the skeletal system.
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Affiliation(s)
- Linyi Liu
- MaineHealth Institute for Research, Scarborough, ME, USA
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He N, Liu M, Wu Y. Adipose tissue and hematopoiesis: Friend or foe? J Clin Lab Anal 2023; 37:e24872. [PMID: 36972475 PMCID: PMC10156104 DOI: 10.1002/jcla.24872] [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: 01/18/2023] [Revised: 03/02/2023] [Accepted: 03/12/2023] [Indexed: 03/29/2023] Open
Abstract
AIM Hematopoietic stem cells are the origin of all hematopoietic cells. They have the self-renewal ability and can differentiate into various blood cells. In physiological state, most of the hematopoietic stem cells are dormant, and only a few cells proliferate to maintain hematopoietic homeostasis. METHODS This precise steady-state maintenance is regulated by complex mechanisms. Bone marrow adipocytes make up half of all cells in the bone marrow cavity, a feature that has attracted the attention of researchers from multiple fields. The adipocyte density within marrow increases during aging and obesity. RESULTS Recent studies have shown that bone marrow adipocytes play important roles in regulating hematopoiesis, but the effects of bone marrow adipocytes on hematopoiesis are often conflicting. Bone marrow adipocytes, participating in the formation of bone marrow hematopoietic microenvironment, influence hematopoiesis positively or negatively. In addition, other adipose tissue, especially white adipose tissue, also regulates hematopoiesis. CONCLUSION In this review, we describe the role of adipose tissue in hematological malignancies, which may be useful for understanding hematopoiesis and the pathogenesis of related diseases.
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Affiliation(s)
- Na He
- Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Min Liu
- Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Yue Wu
- Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China
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Rebeaud M, Bouche C, Dauvillier S, Attané C, Arellano C, Vaysse C, Fallone F, Muller C. A novel 3D culture model for human primary mammary adipocytes to study their metabolic crosstalk with breast cancer in lean and obese conditions. Sci Rep 2023; 13:4707. [PMID: 36949082 PMCID: PMC10033714 DOI: 10.1038/s41598-023-31673-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/15/2023] [Indexed: 03/24/2023] Open
Abstract
Obesity is a negative prognosis factor for breast cancer. Yet, the biological mechanisms underlying this effect are still largely unknown. An emerging hypothesis is that the transfer of free fatty acids (FFA) between adipocytes and tumor cells might be altered under obese conditions, contributing to tumor progression. Currently there is a paucity of models to study human mammary adipocytes (M-Ads)-cancer crosstalk. As for other types of isolated white adipocytes, herein, we showed that human M-Ads die within 2-3 days by necrosis when grown in 2D. As an alternative, M-Ads were grown in a fibrin matrix, a 3D model that preserve their distribution, integrity and metabolic function for up to 5 days at physiological glucose concentrations (5 mM). Higher glucose concentrations frequently used in in vitro models promote lipogenesis during M-Ads culture, impairing their lipolytic function. Using transwell inserts, the matrix embedded adipocytes were cocultured with breast cancer cells. FFA transfer between M-Ads and cancer cells was observed, and this event was amplified by obesity. Together these data show that our 3D model is a new tool for studying the effect of M-Ads on tumor cells and beyond with all the components of the tumor microenvironment including the immune cells.
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Affiliation(s)
- Marie Rebeaud
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
| | - Caroline Bouche
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
- Département de Chirurgie Gynécologique oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France
| | - Stéphanie Dauvillier
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
| | - Camille Attané
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
| | - Carlo Arellano
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
- Département de Chirurgie Gynécologique oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France
| | - Charlotte Vaysse
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
- Département de Chirurgie Gynécologique oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France
| | - Frédérique Fallone
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
| | - Catherine Muller
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France.
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Bone Marrow Adipose Tissue: Regulation of Osteoblastic Niche, Hematopoiesis and Hematological Malignancies. Stem Cell Rev Rep 2023:10.1007/s12015-023-10531-3. [PMID: 36930385 DOI: 10.1007/s12015-023-10531-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2023] [Indexed: 03/18/2023]
Abstract
Bone marrow adipose tissue (BMAT) creates a specific microniche within multifunctional bone marrow (BM) ecosystem which imposes changes in surrounding cells and at systemic level. Moreover, BMAT contributes to spatial and temporal separation and metabolic compartmentalization of BM, thus regulating BM homeostasis and diseases. Recent findings have identified novel progenitor subsets of bone marrow adipocytes (BMAd)s recruited during the BM adipogenesis within different skeletal and hematopoietic stem cell niches. Potential of certain mesenchymal BM cells to differentiate into both osteogenic and adipogenic lineages, contributes to the complex interplay of BMAT with endosteal (osteoblastic) niche compartments as an important cellular player in bone tissue homeostasis. Targeting and ablation of BMAT cells at certain states might be an optional and promising strategy for improvement of bone health. Additionally, recent findings demonstrated spatial distribution of BMAds related to hematopoietic cells and pointed out important functional roles in the vital processes such as long-term hematopoiesis. BM adipogenesis appears to be an emergency phenomenon that follows the production of hematopoietic stem and progenitor cell niche factors, thus regulating physiological, stressed, and malignant hematopoiesis. Lipolytic and secretory activity of BMAds can influence survival and proliferation of hematopoietic cells at different maturation stages. Due to their different lipid status, constitutive and regulated BMAds are important determinants of normal and malignant hematopoietic cells. Further elucidation of cellular and molecular players involved in BMAT expansion and crosstalk with malignant cells is of paramount importance for conceiving the new therapies for improvement of BM health.
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Sawada H, Kazama T, Nagaoka Y, Arai Y, Kano K, Uei H, Tokuhashi Y, Nakanishi K, Matsumoto T. Bone marrow-derived dedifferentiated fat cells exhibit similar phenotype as bone marrow mesenchymal stem cells with high osteogenic differentiation and bone regeneration ability. J Orthop Surg Res 2023; 18:191. [PMID: 36906634 PMCID: PMC10007822 DOI: 10.1186/s13018-023-03678-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 03/04/2023] [Indexed: 03/13/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are known to have different differentiation potential depending on the tissue of origin. Dedifferentiated fat cells (DFATs) are MSC-like multipotent cells that can be prepared from mature adipocytes by ceiling culture method. It is still unknown whether DFATs derived from adipocytes in different tissue showed different phenotype and functional properties. In the present study, we prepared bone marrow (BM)-derived DFATs (BM-DFATs), BM-MSCs, subcutaneous (SC) adipose tissue-derived DFATs (SC-DFATs), and adipose tissue-derived stem cells (ASCs) from donor-matched tissue samples. Then, we compared their phenotypes and multilineage differentiation potential in vitro. We also evaluated in vivo bone regeneration ability of these cells using a mouse femoral fracture model. METHODS BM-DFATs, SC-DFATs, BM-MSCs, and ASCs were prepared from tissue samples of knee osteoarthritis patients who received total knee arthroplasty. Cell surface antigens, gene expression profile, and in vitro differentiation capacity of these cells were determined. In vivo bone regenerative ability of these cells was evaluated by micro-computed tomography imaging at 28 days after local injection of the cells with peptide hydrogel (PHG) in the femoral fracture model in severe combined immunodeficiency mice. RESULTS BM-DFATs were successfully generated at similar efficiency as SC-DFATs. Cell surface antigen and gene expression profiles of BM-DFATs were similar to those of BM-MSCs, whereas these profiles of SC-DFATs were similar to those of ASCs. In vitro differentiation analysis revealed that BM-DFATs and BM-MSCs had higher differentiation tendency toward osteoblasts and lower differentiation tendency toward adipocytes compared to SC-DFATs and ASCs. Transplantation of BM-DFATs and BM-MSCs with PHG enhanced bone mineral density at the injection sites compared to PHG alone in the mouse femoral fracture model. CONCLUSIONS We showed that phenotypic characteristics of BM-DFATs were similar to those of BM-MSCs. BM-DFATs exhibited higher osteogenic differentiation potential and bone regenerative ability compared to SC-DFATs and ASCs. These results suggest that BM-DFATs may be suitable sources of cell-based therapies for patients with nonunion bone fracture.
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Affiliation(s)
- Hirokatsu Sawada
- Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Tomohiko Kazama
- Division of Cell Regeneration and Transplantation, Department of Functional Morphology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-Ku, Tokyo, 173-8610, Japan
| | - Yuki Nagaoka
- Division of Cell Regeneration and Transplantation, Department of Functional Morphology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-Ku, Tokyo, 173-8610, Japan
| | - Yoshinori Arai
- Department of Oral and Maxillofacial Radiology, Nihon University School of Dentistry, Tokyo, Japan
| | - Koichiro Kano
- Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University, Fujisawa, Japan
| | - Hiroshi Uei
- Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuaki Tokuhashi
- Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Kazuyoshi Nakanishi
- Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Taro Matsumoto
- Division of Cell Regeneration and Transplantation, Department of Functional Morphology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-Ku, Tokyo, 173-8610, Japan.
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Ofir N, Mizrakli Y, Greenshpan Y, Gepner Y, Sharabi O, Tsaban G, Zelicha H, Yaskolka Meir A, Ceglarek U, Stumvoll M, Blüher M, Chassidim Y, Rudich A, Reiner-Benaim A, Shai I, Shelef I, Gazit R. Vertebrae but not femur marrow fat transiently decreases in response to body weight loss in an 18-month randomized control trial. Bone 2023; 171:116727. [PMID: 36898571 DOI: 10.1016/j.bone.2023.116727] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 02/06/2023] [Accepted: 03/05/2023] [Indexed: 03/11/2023]
Abstract
BACKGROUND Increased levels of bone marrow adipose tissue (BMAT) are negatively associated with skeletal health and hematopoiesis. BMAT is known to increase with age; however, the effect of long-term weight loss on BMAT is still unknown. OBJECTIVE In this study, we examined BMAT response to lifestyle-induced weight loss in 138 participants (mean age 48 y; mean body mass index 31 kg/m2), who participated in the CENTRAL-MRI trial. METHODS Participants were randomized for dietary intervention of low-fat or low-carb, with or without physical activity. Magnetic resonance imaging (MRI) was used to quantify BMAT and other fat depots at baseline, six and eighteen months of intervention. Blood biomarkers were also measured at the same time points. RESULTS At baseline, the L3 vertebrae BMAT is positively associated with age, HDL cholesterol, HbA1c and adiponectin; but not with other fat depots or other metabolic markers tested. Following six months of dietary intervention, the L3 BMAT declined by an average of 3.1 %, followed by a return to baseline after eighteen months (p < 0.001 and p = 0.189 compared to baseline, respectively). The decrease of BMAT during the first six months was associated with a decrease in waist circumference, cholesterol, proximal-femur BMAT, and superficial subcutaneous adipose tissue (SAT), as well as with younger age. Nevertheless, BMAT changes did not correlate with changes in other fat depots. CONCLUSIONS We conclude that physiological weight loss can transiently reduce BMAT in adults, and this effect is more prominent in younger adults. Our findings suggest that BMAT storage and dynamics are largely independent of other fat depots or cardio-metabolic risk markers, highlighting its unique functions.
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Affiliation(s)
- Noa Ofir
- The Shraga Segal Department for Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Yuval Mizrakli
- The Shraga Segal Department for Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel
| | - Yariv Greenshpan
- The Shraga Segal Department for Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Yftach Gepner
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel; Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Sylvan Adams Sports Institute, Tel-Aviv University, Tel-Aviv, Israel
| | - Omri Sharabi
- The Shraga Segal Department for Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Gal Tsaban
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Hila Zelicha
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Anat Yaskolka Meir
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Uta Ceglarek
- Institute of Laboratory Medicine, University of Leipzig Medical Center, Germany
| | | | | | | | - Assaf Rudich
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Anat Reiner-Benaim
- Department of Epidemiology, Biostatistics and Community Health Sciences, School of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel
| | - Iris Shai
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Ilan Shelef
- Soroka University Medical Center, Beer-Sheva, Israel
| | - Roi Gazit
- The Shraga Segal Department for Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
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Kim DY, Ko SH. Common Regulators of Lipid Metabolism and Bone Marrow Adiposity in Postmenopausal Women. Pharmaceuticals (Basel) 2023; 16:322. [PMID: 37259464 PMCID: PMC9967016 DOI: 10.3390/ph16020322] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 09/13/2024] Open
Abstract
A variety of metabolic disorders are associated with a decrease in estradiol (E2) during natural or surgical menopause. Postmenopausal women are prone to excessive fat accumulation in skeletal muscle and adipose tissue due to the loss of E2 via abnormalities in lipid metabolism and serum lipid levels. In skeletal muscle and adipose tissue, genes related to energy metabolism and fatty acid oxidation, such as those encoding peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and estrogen-related receptor alpha (ERRα), are downregulated, leading to increased fat synthesis and lipid metabolite accumulation. The same genes regulate lipid metabolism abnormalities in the bone marrow. In this review, abnormalities in lipid metabolism caused by E2 deficiency were investigated, with a focus on genes able to simultaneously regulate not only skeletal muscle and adipose tissue but also bone metabolism (e.g., genes encoding PGC-1α and ERRα). In addition, the mechanisms through which mesenchymal stem cells lead to adipocyte differentiation in the bone marrow as well as metabolic processes related to bone marrow adiposity, bone loss, and osteoporosis were evaluated, focusing on the loss of E2 and lipid metabolic alterations. The work reviewed here suggests that genes underlying lipid metabolism and bone marrow adiposity are candidate therapeutic targets for bone loss and osteoporosis in postmenopausal women.
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Affiliation(s)
- Dae-Yong Kim
- CEO, N- BIOTEK, Inc., 402-803, Technopark, 655, Pyeongcheon-ro, Bucheon-si 14502, Gyeonggi-do, Republic of Korea
| | - Seong-Hee Ko
- Regenerative Medicine Research Team, N- BIOTEK, Inc., 104-706, Technopark Ssangyong 3Cha, 397, Seokcheon-ro, Bucheon-si 14449, Gyeonggi-do, Republic of Korea
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Beekman KM, Duque G, Corsi A, Tencerova M, Bisschop PH, Paccou J. Osteoporosis and Bone Marrow Adipose Tissue. Curr Osteoporos Rep 2023; 21:45-55. [PMID: 36534306 DOI: 10.1007/s11914-022-00768-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/17/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW This review focuses on the recent findings regarding bone marrow adipose tissue (BMAT) concerning bone health. We summarize the variations in BMAT in relation to age, sex, and skeletal sites, and provide an update on noninvasive imaging techniques to quantify human BMAT. Next, we discuss the role of BMAT in patients with osteoporosis and interventions that affect BMAT. RECENT FINDINGS There are wide individual variations with region-specific fluctuation and age- and gender-specific differences in BMAT content and composition. The Bone Marrow Adiposity Society (BMAS) recommendations aim to standardize imaging protocols to increase comparability across studies and sites. Water-fat imaging (WFI) seems an accurate and efficient alternative for spectroscopy (1H-MRS). Most studies indicate that greater BMAT is associated with lower bone mineral density (BMD) and a higher prevalence of vertebral fractures. The proton density fat fraction (PDFF) and changes in lipid composition have been associated with an increased risk of fractures independently of BMD. Therefore, PDFF and lipid composition could potentially be future imaging biomarkers for assessing fracture risk. Evidence of the inhibitory effect of osteoporosis treatments on BMAT is still limited to a few randomized controlled trials. Moreover, results from the FRAME biopsy sub-study highlight contradictory findings on the effect of the sclerostin antibody romosozumab on BMAT. Further understanding of the role(s) of BMAT will provide insight into the pathogenesis of osteoporosis and may lead to targeted preventive and therapeutic strategies.
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Affiliation(s)
- Kerensa M Beekman
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Gustavo Duque
- Department of Medicine and Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Michaela Tencerova
- Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Peter H Bisschop
- Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Julien Paccou
- Department of Rheumatology, MABLaB ULR 4490, CHU Lille, University Lille, Lille, France.
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Fairfield H, Condruti R, Farrell M, Di Iorio R, Gartner CA, Vary C, Reagan MR. Development and characterization of three cell culture systems to investigate the relationship between primary bone marrow adipocytes and myeloma cells. Front Oncol 2023; 12:912834. [PMID: 36713534 PMCID: PMC9874147 DOI: 10.3389/fonc.2022.912834] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 11/21/2022] [Indexed: 01/12/2023] Open
Abstract
The unique properties of the bone marrow (BM) allow for migration and proliferation of multiple myeloma (MM) cells while also providing the perfect environment for development of quiescent, drug-resistant MM cell clones. BM adipocytes (BMAds) have recently been identified as important contributors to systemic adipokine levels, bone strength, hematopoiesis, and progression of metastatic and primary BM cancers, such as MM. Recent studies in myeloma suggest that BMAds can be reprogrammed by tumor cells to contribute to myeloma-induced bone disease, and, reciprocally, BMAds support MM cells in vitro. Importantly, most data investigating BMAds have been generated using adipocytes generated by differentiating BM-derived mesenchymal stromal cells (BMSCs) into adipocytes in vitro using adipogenic media, due to the extreme technical challenges associated with isolating and culturing primary adipocytes. However, if studies could be performed with primary adipocytes, then they likely will recapitulate in vivo biology better than BMSC-derived adipocytes, as the differentiation process is artificial and differs from in vivo differentiation, and progenitor cell(s) of the primary BMAd (pBMAds) may not be the same as the BMSCs precursors used for adipogenic differentiation in vitro. Therefore, we developed and refined three methods for culturing pBMAds: two-dimensional (2D) coverslips, 2D transwells, and three-dimensional (3D) silk scaffolds, all of which can be cultured alone or with MM cells to investigate bidirectional tumor-host signaling. To develop an in vitro model with a tissue-like structure to mimic the BM microenvironment, we developed the first 3D, tissue engineered model utilizing pBMAds derived from human BM. We found that pBMAds, which are extremely fragile, can be isolated and stably cultured in 2D for 10 days and in 3D for up to 4 week in vitro. To investigate the relationship between pBMAds and myeloma, MM cells can be added to investigate physical relationships through confocal imaging and soluble signaling molecules via mass spectrometry. In summary, we developed three in vitro cell culture systems to study pBMAds and myeloma cells, which could be adapted to investigate many diseases and biological processes involving the BM, including other bone-homing tumor types.
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Affiliation(s)
- Heather Fairfield
- MaineHealth Institute for Research, Scarborough, ME, United States,University of Maine Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, United States,Tufts University School of Medicine, Boston, MA, United States
| | | | - Mariah Farrell
- MaineHealth Institute for Research, Scarborough, ME, United States,University of Maine Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, United States,Tufts University School of Medicine, Boston, MA, United States
| | - Reagan Di Iorio
- MaineHealth Institute for Research, Scarborough, ME, United States,University of New England, Biddeford, ME, United States
| | - Carlos A. Gartner
- MaineHealth Institute for Research, Scarborough, ME, United States,University of Maine Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, United States,Tufts University School of Medicine, Boston, MA, United States
| | - Calvin Vary
- MaineHealth Institute for Research, Scarborough, ME, United States,University of Maine Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, United States,Tufts University School of Medicine, Boston, MA, United States
| | - Michaela R. Reagan
- MaineHealth Institute for Research, Scarborough, ME, United States,University of Maine Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, United States,Tufts University School of Medicine, Boston, MA, United States,*Correspondence: Michaela R. Reagan,
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Zheng Y, Rajcsanyi LS, Kowalczyk M, Giuranna J, Herpertz-Dahlmann B, Seitz J, de Zwaan M, Herzog W, Ehrlich S, Zipfel S, Giel K, Egberts K, Burghardt R, Föcker M, Al-Lahham S, Hebebrand J, Fuhrer D, Tan S, Zwanziger D, Peters T, Hinney A. Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals. Front Endocrinol (Lausanne) 2023; 14:1137308. [PMID: 37025415 PMCID: PMC10071025 DOI: 10.3389/fendo.2023.1137308] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/09/2023] [Indexed: 04/08/2023] Open
Abstract
CONTEXT The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway. OBJECTIVE We aimed to (i) detect variants in the lipocalin-2 gene (LCN2) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level. METHODS Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R, and 33 matched controls without NSVs in the two genes. RESULTS Fourteen LCN2-variants (five NSVs) were detected. LCN2-p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity (p = 0.033). CONCLUSION Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2-variants might have a profound effect on lipocalin-2 levels.
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Affiliation(s)
- Yiran Zheng
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Yiran Zheng,
| | - Luisa Sophie Rajcsanyi
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Manuela Kowalczyk
- Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry – Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Johanna Giuranna
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Beate Herpertz-Dahlmann
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany
| | - Jochen Seitz
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany
| | - Martina de Zwaan
- Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Wolfgang Herzog
- Department of Internal Medicine II, General Internal and Psychosomatic Medicine, University of Heidelberg, Heidelberg, Germany
| | - Stefan Ehrlich
- Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, TU-Dresden, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
- Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Stephan Zipfel
- Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital, Tübingen, Germany
- Centre of Excellence for Eating Disorders, University of Tübingen, Tübingen, Germany
| | - Katrin Giel
- Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital, Tübingen, Germany
- Centre of Excellence for Eating Disorders, University of Tübingen, Tübingen, Germany
| | - Karin Egberts
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
| | - Roland Burghardt
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Oberberg Fachklinik Fasanenkiez, Berlin, Germany
| | - Manuel Föcker
- Department of Child and Adolescent Psychiatry, University of Münster, Münster, Germany
| | - Saad Al-Lahham
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
| | - Johannes Hebebrand
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Dagmar Fuhrer
- Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry – Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Susanne Tan
- Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Denise Zwanziger
- Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry – Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Triinu Peters
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anke Hinney
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Thapa S, Nandy A, Rendina-Ruedy E. Endocrinal metabolic regulation on the skeletal system in post-menopausal women. Front Physiol 2022; 13:1052429. [PMID: 36439254 PMCID: PMC9691779 DOI: 10.3389/fphys.2022.1052429] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 10/27/2022] [Indexed: 08/13/2023] Open
Abstract
Osteoporosis is a common endocrinologic disorder characterized as a chronic bone loss condition. Sexual dimorphism is ubiquitous in the incidence of osteoporosis with post-menopausal women being acutely affected. Gonadal sex hormones including estrogen act as crucial regulators of bone mass; therefore, loss of such hormones leads to an imbalance in skeletal turnover leading to osteoporosis. Estrogen can influence both bone formation as well as resorption by reducing osteoblast activity and enhancing osteoclastogenesis. Additionally, estrogen is a potent regulator of systemic metabolism. Recent studies have provided clues that estrogenic effect on bone might also involve alterations in bone cell metabolism and bioenergetic potential. While direct effects of gonadal hormones ability to alter intracellular metabolism of bone cells has not been studied, there is precedence within the literature that this is occurring and contributing to post-menopausal bone loss. This review aims to serve as a perspective piece detailing the prospective role of gonadal hormones regulating bone cell metabolic potential.
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Affiliation(s)
- Santosh Thapa
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Ananya Nandy
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Elizabeth Rendina-Ruedy
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
- Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
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Vauclard A, Bellio M, Valet C, Borret M, Payrastre B, Severin S. Obesity: Effects on bone marrow homeostasis and platelet activation. Thromb Res 2022. [DOI: 10.1016/j.thromres.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Interplay between Prostate Cancer and Adipose Microenvironment: A Complex and Flexible Scenario. Int J Mol Sci 2022; 23:ijms231810762. [PMID: 36142673 PMCID: PMC9500873 DOI: 10.3390/ijms231810762] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/09/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
Adipose tissue is part of the prostate cancer (PCa) microenvironment not only in the periprostatic area, but also in the most frequent metastatic sites, such as bone marrow and pelvic lymph nodes. The involvement of periprostatic adipose tissue (PPAT) in the aggressiveness of PCa is strongly suggested by numerous studies. Many molecules play a role in the reciprocal interaction between adipocytes and PCa cells, including adipokines, hormones, lipids, and also lipophilic pollutants stored in adipocytes. The crosstalk has consequences not only on cancer cell growth and metastatic potential, but also on adipocytes. Although most of the molecules released by PPAT are likely to promote tumor growth and the migration of cancer cells, others, such as the adipokine adiponectin and the n-6 or n-3 polyunsaturated fatty acids (PUFAs), have been shown to have anti-tumor properties. The effects of PPAT on PCa cells might therefore depend on the balance between the pro- and anti-tumor components of PPAT. In addition, genetic and environmental factors involved in the risk and/or aggressiveness of PCa, including obesity and diet, are able to modulate the interactions between PPAT and cancer cells and their consequences on the growth and the metastatic potential of PCa.
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Wu Y, Li X, Li Q, Cheng C, Zheng L. Adipose tissue-to-breast cancer crosstalk: Comprehensive insights. Biochim Biophys Acta Rev Cancer 2022; 1877:188800. [PMID: 36103907 DOI: 10.1016/j.bbcan.2022.188800] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/29/2022] [Accepted: 09/06/2022] [Indexed: 10/14/2022]
Abstract
The review focuses on mechanistic evidence for the link between obesity and breast cancer. According to the IARC study, there is sufficient evidence that obesity is closely related to a variety of cancers. Among them, breast cancer is particularly disturbed by adipose tissue due to the unique histological structure of the breast. The review introduces the relationship between obesity and breast cancer from two aspects, including factors that promote tumorigenesis or metastasis. We summarize alterations in adipokines and metabolic pathways that contribute to breast cancer development. Breast cancer metastasis is closely related to obesity-induced pro-inflammatory microenvironment, adipose stem cells, and miRNAs. Based on the mechanism by which obesity causes breast cancer, we list possible therapeutic directions, including reducing the risk of breast cancer and inhibiting the progression of breast cancer. We also discussed the risk of autologous breast remodeling and fat transplantation. Finally, the causes of the obesity paradox and the function of enhancing immunity are discussed. Evaluating the balance between obesity-induced inflammation and enhanced immunity warrants further study.
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Affiliation(s)
- Yuan Wu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Xu Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, PR China
| | - Qiong Li
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Chienshan Cheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Lan Zheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China.
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Hernandez M, Shin S, Muller C, Attané C. The role of bone marrow adipocytes in cancer progression: the impact of obesity. Cancer Metastasis Rev 2022; 41:589-605. [PMID: 35708800 DOI: 10.1007/s10555-022-10042-6] [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: 02/19/2022] [Accepted: 05/27/2022] [Indexed: 11/27/2022]
Abstract
Bone marrow adipose tissues (BMATs) and their main cellular component, bone marrow adipocytes (BMAds), are found within the bone marrow (BM), which is a niche for the development of hematological malignancies as well as bone metastasis from solid tumors such as breast and prostate cancers. In humans, BMAds are present within the hematopoietic or "red" BMAT and in the "yellow" BMAT where they are more densely packed. BMAds are emerging as new actors in tumor progression; however, there are many outstanding questions regarding their precise role. In this review, we summarized our current knowledge regarding the development, distribution, and regulation by external stimuli of the BMATs in mice and humans and addressed how obesity could affect these traits. We then discussed the specific metabolic phenotype of BMAds that appear to be different from "classical" white adipocytes, since they are devoid of lipolytic function. According to this characterization, we presented how tumor cells affect the in vitro and in vivo phenotype of BMAds and the signals emanating from BMAds that are susceptible to modulate tumor behavior with a specific emphasis on their metabolic crosstalk with cancer cells. Finally, we discussed how obesity could affect this crosstalk. Deciphering the role of BMAds in tumor progression would certainly lead to the identification of new targets in oncology in the near future.
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Affiliation(s)
- Marine Hernandez
- Institut de Pharmacologie Et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
- Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France
| | - Sauyeun Shin
- Institut de Pharmacologie Et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
- Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France
| | - Catherine Muller
- Institut de Pharmacologie Et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
- Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
| | - Camille Attané
- Institut de Pharmacologie Et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
- Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
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Pachón-Peña G, Bredella MA. Bone marrow adipose tissue in metabolic health. Trends Endocrinol Metab 2022; 33:401-408. [PMID: 35396163 PMCID: PMC9098665 DOI: 10.1016/j.tem.2022.03.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/25/2022] [Accepted: 03/10/2022] [Indexed: 10/18/2022]
Abstract
Recent studies have highlighted the role of bone marrow adipose tissue (BMAT) as a regulator of skeletal homeostasis and energy metabolism. While long considered an inert filler, occupying empty spaces from bone loss and reduced hematopoiesis, BMAT is now considered a secretory and metabolic organ that responds to nutritional challenges and secretes cytokines, which indirectly impact energy and bone metabolism. The recent advances in our understanding of the function of BMAT have been enabled by novel noninvasive imaging techniques, which allow longitudinal assessment of BMAT in vivo following interventions. This review will focus on the latest advances in our understanding of BMAT and its role in metabolic health. Imaging techniques to quantify the content and composition of BMAT will be discussed.
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Affiliation(s)
| | - Miriam A Bredella
- Division of Musculoskeletal Imaging and Intervention, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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Hughes AM, Kuek V, Kotecha RS, Cheung LC. The Bone Marrow Microenvironment in B-Cell Development and Malignancy. Cancers (Basel) 2022; 14:2089. [PMID: 35565219 PMCID: PMC9102980 DOI: 10.3390/cancers14092089] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/11/2022] [Accepted: 04/20/2022] [Indexed: 11/16/2022] Open
Abstract
B lymphopoiesis is characterized by progressive loss of multipotent potential in hematopoietic stem cells, followed by commitment to differentiate into B cells, which mediate the humoral response of the adaptive immune system. This process is tightly regulated by spatially distinct bone marrow niches where cells, including mesenchymal stem and progenitor cells, endothelial cells, osteoblasts, osteoclasts, and adipocytes, interact with B-cell progenitors to direct their proliferation and differentiation. Recently, the B-cell niche has been implicated in initiating and facilitating B-cell precursor acute lymphoblastic leukemia. Leukemic cells are also capable of remodeling the B-cell niche to promote their growth and survival and evade treatment. Here, we discuss the major cellular components of bone marrow niches for B lymphopoiesis and the role of the malignant B-cell niche in disease development, treatment resistance and relapse. Further understanding of the crosstalk between leukemic cells and bone marrow niche cells will enable development of additional therapeutic strategies that target the niches in order to hinder leukemia progression.
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Affiliation(s)
- Anastasia M. Hughes
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
| | - Vincent Kuek
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Rishi S. Kotecha
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- School of Medicine, University of Western Australia, Perth, WA 6009, Australia
- Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, WA 6009, Australia
| | - Laurence C. Cheung
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
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Collins N, Belkaid Y. Control of immunity via nutritional interventions. Immunity 2022; 55:210-223. [PMID: 35139351 DOI: 10.1016/j.immuni.2022.01.004] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/29/2021] [Accepted: 01/05/2022] [Indexed: 12/18/2022]
Abstract
Nutrition affects all physiological processes including those linked to the development and function of our immune system. Here, we discuss recent evidence and emerging concepts supporting the idea that our newfound relationship with nutrition in industrialized countries has fundamentally altered the way in which our immune system is wired. This will be examined through the lens of studies showing that mild or transient reductions in dietary intake can enhance protective immunity while also limiting aberrant inflammatory responses. We will further discuss how trade-offs and priorities begin to emerge in the context of severe nutritional stress. In those settings, specific immunological functions are heightened to re-enforce processes and tissue sites most critical to survival. Altogether, these examples will emphasize the profound influence nutrition has over the immune system and highlight how a mechanistic exploration of this cross talk could ultimately lead to the design of novel therapeutic approaches that prevent and treat disease.
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Affiliation(s)
- Nicholas Collins
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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Matsushita Y, Ono W, Ono N. Toward Marrow Adipocytes: Adipogenic Trajectory of the Bone Marrow Stromal Cell Lineage. Front Endocrinol (Lausanne) 2022; 13:882297. [PMID: 35528017 PMCID: PMC9075612 DOI: 10.3389/fendo.2022.882297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 03/24/2022] [Indexed: 11/13/2022] Open
Abstract
Bone marrow contains precursor cells for osteoblasts and adipocytes in the stromal compartment. Bone marrow adipose tissue (BMAT) is an important constituent of the bone marrow that is particularly abundant in adults. BMAT is composed of the proximal "regulated" BMAT containing individual adipocytes interspersed within actively hematopoietic marrow, and the distal "constitutive" BMAT containing large adipocytes in the area of low hematopoiesis. Historically, bone marrow adipocytes were regarded as one of the terminal states of skeletal stem cells, which stand at the pinnacle of the lineage and possess trilineage differentiation potential into osteoblasts, chondrocytes and adipocytes. Recent single-cell RNA-sequencing studies uncover a discrete group of preadipocyte-like cells among bone marrow stromal cells (BMSCs), and recent mouse genetic lineage-tracing studies reveal that these adipocyte precursor cells possess diverse functions in homeostasis and regeneration. These adipogenic subsets of BMSCs are abundant in the central marrow space and can directly convert not only into lipid-laden adipocytes but also into skeletal stem cell-like cells and osteoblasts under regenerative conditions. It remains determined whether there are distinct adipocyte precursor cell types contributing to two types of BMATs. In this short review, we discuss the functions of the recently identified subsets of BMSCs and their trajectory toward marrow adipocytes, which is influenced by multiple modes of cell-autonomous and non-cell autonomous regulations.
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