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Metabolism: Clinical and Experimental Mar 2024Disturbance in the differentiation process of bone marrow mesenchymal stem cells (BMSCs) leads to osteoporosis. Mitochondrial dynamics plays a pivotal role in the...
BACKGROUND
Disturbance in the differentiation process of bone marrow mesenchymal stem cells (BMSCs) leads to osteoporosis. Mitochondrial dynamics plays a pivotal role in the metabolism and differentiation of BMSCs. However, the mechanisms underlying mitochondrial dynamics and their impact on the differentiation equilibrium of BMSCs remain unclear.
METHODS
We investigated the mitochondrial morphology and markers related to mitochondrial dynamics during BMSCs osteogenic and adipogenic differentiation. Bioinformatics was used to screen potential genes regulating BMSCs differentiation through mitochondrial dynamics. Subsequently, we evaluated the impact of Transmembrane protein 135 (TMEM135) deficiency on bone homeostasis by comparing Tmem135 knockout mice with their littermates. The mechanism of TMEM135 in mitochondrial dynamics and BMSCs differentiation was also investigated in vivo and in vitro.
RESULTS
Distinct changes in mitochondrial morphology were observed between osteogenic and adipogenic differentiation of BMSCs, manifesting as fission in the late stage of osteogenesis and fusion in adipogenesis. Additionally, we revealed that TMEM135, a modulator of mitochondrial dynamics, played a functional role in regulating the equilibrium between adipogenesis and osteogenesis. The TMEM135 deficiency impaired mitochondrial fission and disrupted crucial mitochondrial energy metabolism during osteogenesis. Tmem135 knockout mice showed osteoporotic phenotype, characterized by reduced osteogenesis and increased adipogenesis. Mechanistically, TMEM135 maintained intracellular calcium ion homeostasis and facilitated the dephosphorylation of dynamic-related protein 1 at Serine 637 in BMSCs.
CONCLUSIONS
Our findings underscore the significant role of TMEM135 as a modulator in orchestrating the differentiation trajectory of BMSCs and promoting a shift in mitochondrial dynamics toward fission. This ultimately contributes to the osteogenesis process. This work has provided promising biological targets for the treatment of osteoporosis.
Topics: Animals; Mice; Adipogenesis; Cell Differentiation; Cells, Cultured; Mice, Knockout; Mitochondrial Dynamics; Osteogenesis; Osteoporosis
PubMed: 38154611
DOI: 10.1016/j.metabol.2023.155767 -
Genes Jan 2024Pericytes (PCs) are located surrounding the walls of small blood vessels, particularly capillaries and microvessels. In addition to their functions in maintaining... (Review)
Review
Pericytes (PCs) are located surrounding the walls of small blood vessels, particularly capillaries and microvessels. In addition to their functions in maintaining vascular integrity, participating in angiogenesis, and regulating blood flow, PCs also serve as a reservoir for multi-potent stem/progenitor cells in white, brown, beige, and bone marrow adipose tissues. Due to the complex nature of this cell population, the identification and characterization of PCs has been challenging. A comprehensive understanding of the heterogeneity of PCs may enhance their potential as therapeutic targets for metabolic syndromes or bone-related diseases. This mini-review summarizes multiple PC markers commonly employed in lineage-tracing studies, with an emphasis on their contribution to adipogenesis and functions in different adipose depots under diverse metabolic conditions.
Topics: Adipogenesis; Pericytes; Adipose Tissue; Stem Cells; Capillaries
PubMed: 38275607
DOI: 10.3390/genes15010126 -
Acta Neuropathologica Nov 2023Inclusion body myositis (IBM) is unique across the spectrum of idiopathic inflammatory myopathies (IIM) due to its distinct clinical presentation and refractoriness to...
Inclusion body myositis (IBM) is unique across the spectrum of idiopathic inflammatory myopathies (IIM) due to its distinct clinical presentation and refractoriness to current treatment approaches. One explanation for this resistance may be the engagement of cell-autonomous mechanisms that sustain or promote disease progression of IBM independent of inflammatory activity. In this study, we focused on senescence of tissue-resident cells as potential driver of disease. For this purpose, we compared IBM patients to non-diseased controls and immune-mediated necrotizing myopathy patients. Histopathological analysis suggested that cellular senescence is a prominent feature of IBM, primarily affecting non-myogenic cells. In-depth analysis by single nuclei RNA sequencing allowed for the deconvolution and study of muscle-resident cell populations. Among these, we identified a specific cluster of fibro-adipogenic progenitors (FAPs) that demonstrated key hallmarks of senescence, including a pro-inflammatory secretome, expression of p21, increased β-galactosidase activity, and engagement of senescence pathways. FAP function is required for muscle cell health with changes to their phenotype potentially proving detrimental. In this respect, the transcriptomic landscape of IBM was also characterized by changes to the myogenic compartment demonstrating a pronounced loss of type 2A myofibers and a rarefication of acetylcholine receptor expressing myofibers. IBM muscle cells also engaged a specific pro-inflammatory phenotype defined by intracellular complement activity and the expression of immunogenic surface molecules. Skeletal muscle cell dysfunction may be linked to FAP senescence by a change in the collagen composition of the latter. Senescent FAPs lose collagen type XV expression, which is required to support myofibers' structural integrity and neuromuscular junction formation in vitro. Taken together, this study demonstrates an altered phenotypical landscape of muscle-resident cells and that FAPs, and not myofibers, are the primary senescent cell type in IBM.
Topics: Humans; Myositis, Inclusion Body; Adipogenesis; Myositis; Collagen; Muscle, Skeletal
PubMed: 37773216
DOI: 10.1007/s00401-023-02637-2 -
Advanced Science (Weinheim,... Nov 2023Obesity and type 2 diabetes are becoming a global sociobiomedical burden. Beige adipocytes are emerging as key inducible actors and putative relevant therapeutic targets...
Obesity and type 2 diabetes are becoming a global sociobiomedical burden. Beige adipocytes are emerging as key inducible actors and putative relevant therapeutic targets for improving metabolic health. However, in vitro models of human beige adipose tissue are currently lacking and hinder research into this cell type and biotherapy development. Unlike traditional bottom-up engineering approaches that aim to generate building blocks, here a scalable system is proposed to generate pre-vascularized and functional human beige adipose tissue organoids using the human stromal vascular fraction of white adipose tissue as a source of adipose and endothelial progenitors. This engineered method uses a defined biomechanical and chemical environment using tumor growth factor β (TGFβ) pathway inhibition and specific gelatin methacryloyl (GelMA) embedding parameters to promote the self-organization of spheroids in GelMA hydrogel, facilitating beige adipogenesis and vascularization. The resulting vascularized organoids display key features of native beige adipose tissue including inducible Uncoupling Protein-1 (UCP1) expression, increased uncoupled mitochondrial respiration, and batokines secretion. The controlled assembly of spheroids allows to translate organoid morphogenesis to a macroscopic scale, generating vascularized centimeter-scale beige adipose micro-tissues. This approach represents a significant advancement in developing in vitro human beige adipose tissue models and facilitates broad applications ranging from basic research to biotherapies.
Topics: Humans; Diabetes Mellitus, Type 2; Obesity; Adipogenesis; Adipose Tissue, White; Organoids
PubMed: 37731092
DOI: 10.1002/advs.202301499 -
Genes & Development Sep 2023Adipose tissue exhibits a remarkable capacity to expand, contract, and remodel in response to changes in physiological and environmental conditions. Here, we describe... (Review)
Review
Adipose tissue exhibits a remarkable capacity to expand, contract, and remodel in response to changes in physiological and environmental conditions. Here, we describe recent advances in our understanding of how functionally distinct tissue-resident mesenchymal stromal cell subpopulations orchestrate several aspects of physiological and pathophysiological adipose tissue remodeling, with a particular focus on the adaptations that occur in response to changes in energy surplus and environmental temperature. The study of adipose tissue remodeling provides a vehicle to understand the functional diversity of stromal cells and offers a lens through which several generalizable aspects of tissue reorganization can be readily observed.
Topics: Humans; Adipogenesis; Adipose Tissue; Mesenchymal Stem Cells; Obesity; Stromal Cells
PubMed: 37798016
DOI: 10.1101/gad.351069.123 -
Stem Cell Research & Therapy Nov 2023Macrophage polarization has been observed in the process of muscle injuries including rotator cuff (RC) muscle atrophy and fatty infiltration after large tendon tears....
BACKGROUND
Macrophage polarization has been observed in the process of muscle injuries including rotator cuff (RC) muscle atrophy and fatty infiltration after large tendon tears. In our previous study, we showed that fibrogenesis and white adipogenesis of muscle residential fibro/adipogenic progenitors (FAPs) cause fibrosis and fatty infiltration and that brown/beige adipogenesis of FAPs promotes rotator cuff muscle regeneration. However, how polarized macrophages and their exosomes regulate FAP differentiation remains unknown.
METHODS
We cultured FAPs with M0, M1, and M2 macrophages or 2 × 10 exosomes derived from M0, M1 and M2 with and without GW4869, an exosome inhibitor. In vivo, M0, M1, and M2 macrophages were transplanted or purified macrophage exosomes (M0, M1, M2) were injected into supraspinatus muscle (SS) after massive tendon tears in mice (n = 6). SS were harvested at six weeks after surgery to evaluate the level of muscle atrophy and fatty infiltration.
RESULTS
Our results showed that M2 rather than M0 or M1 macrophages stimulates brown/beige fat differentiation of FAPs. However, the effect of GW4869, the exosome inhibitor, diminished this effect. M2 exosomes also promoted FAP Beige differentiation in vitro. The transplantation of M2 macrophages reduced supraspinatus muscle atrophy and fatty infiltration. In vivo injections of M2 exosomes significantly reduced muscle atrophy and fatty infiltration in supraspinatus muscle.
CONCLUSION
Results from our study demonstrated that polarized macrophages directly regulated FAP differentiation through their exosomes and M2 macrophage-derived exosomes may serve as a novel treatment option for RC muscle atrophy and fatty infiltration.
Topics: Mice; Animals; Adipogenesis; Exosomes; Rotator Cuff; Muscular Atrophy; Macrophages
PubMed: 37936229
DOI: 10.1186/s13287-023-03555-6 -
BioRxiv : the Preprint Server For... Feb 2024The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by...
The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process. We found that aging increases the expression of and other fibro-inflammatory genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes. Fibroblastic ASPC populations from young and aged mice were equally competent for beige differentiation , suggesting that environmental factors suppress adipogenesis . Examination of adipocytes by single nucleus RNA-sequencing identified compositional and transcriptional differences in adipocyte populations with age and cold exposure. Notably, cold exposure induced an adipocyte population expressing high levels of lipogenesis (DNL) genes, and this response was severely blunted in aged animals. We further identified natriuretic peptide clearance receptor , a beige fat repressor, as a marker gene for a subset of white adipocytes and an aging-upregulated gene in adipocytes. In summary, this study indicates that aging blocks beige adipogenesis and dysregulates adipocyte responses to cold exposure and provides a unique resource for identifying cold and aging-regulated pathways in adipose tissue.
PubMed: 36993336
DOI: 10.1101/2023.03.20.533514 -
IScience Oct 2023Circular RNA (circRNA) is a special category of non-coding RNA that has garnered increasing attention in the exploration of lipid metabolism. However, the functional...
Circular RNA (circRNA) is a special category of non-coding RNA that has garnered increasing attention in the exploration of lipid metabolism. However, the functional regulation mechanisms of circRNAs in obesity diseases remain unclear. By whole transcriptome sequencing, a total of 164 circular RNAs were found to exhibit differential expression between lean and obese individuals. RT-qPCR was used to detect significant expression of circMAPK9 in obese individuals, and it was closely related to BMI. Western blot, triglyceride detection, and Oil Red O staining were employed to investigate the role of circMAPK9/hsa-miR-1322/FTO in adipogenesis. In adipocytes, the connection between hsa-miR-1322 and circMAPK9 was verified using fluorescence hybridization, luciferase reporter assay, and RNA immunoprecipitation. It was found that circMAPK9 competed for binding hsa-miR-1322 in the cytoplasm, weakening the inhibitory effect on FTO and promoting adipogenesis. Our study revealed the regulatory mechanism and important role of circMAPK9 in the process of adipogenesis.
PubMed: 37692283
DOI: 10.1016/j.isci.2023.107756 -
American Journal of Physiology. Cell... Oct 2023Fibro-adipogenic progenitors (FAPs) are key regulators of skeletal muscle regeneration and homeostasis. However, dysregulation of these cells leads to fibro-fatty... (Review)
Review
Fibro-adipogenic progenitors (FAPs) are key regulators of skeletal muscle regeneration and homeostasis. However, dysregulation of these cells leads to fibro-fatty infiltration across various muscle diseases. FAPs are the key source of extracellular matrix (ECM) deposition in muscle, and disruption to this process leads to a pathological accumulation of ECM, known as fibrosis. The replacement of contractile tissue with fibrotic ECM functionally impairs the muscle and increases muscle stiffness. FAPs and fibrotic muscle form a progressively degenerative feedback loop where, as a muscle becomes fibrotic, it induces a fibrotic FAP phenotype leading to further development of fibrosis. In this review, we summarize FAPs' role in fibrosis in terms of their activation, heterogeneity, contributions to fibrotic degeneration, and role across musculoskeletal diseases. We also discuss current research on potential therapeutic avenues to attenuate fibrosis by targeting FAPs.
Topics: Humans; Adipogenesis; Adipocytes; Stem Cells; Fibrosis; Muscle, Skeletal; Cell Differentiation
PubMed: 37602412
DOI: 10.1152/ajpcell.00245.2023 -
Obesity Reviews : An Official Journal... Jan 2024Iron plays a vital role in essential biological processes and requires precise regulation within the body. Dysregulation of iron homeostasis, characterized by increased... (Review)
Review
Iron plays a vital role in essential biological processes and requires precise regulation within the body. Dysregulation of iron homeostasis, characterized by increased serum ferritin levels and excessive accumulation of iron in the liver, adipose tissue, and skeletal muscle, is associated with obesity and insulin resistance. Notably, iron excess in adipose tissue promotes adipose tissue dysfunction. As optimal adipose tissue function is crucial for maintaining a healthy phenotype in obesity, a comprehensive understanding of iron homeostasis in adipose tissue is imperative for designing new therapeutic approaches to improve and prevent adipose tissue dysfunction. Here, we conducted a review of relevant studies, focusing on and providing valuable insights into the intricate interplay between iron and adipose tissue. It sheds light on the impact of iron on adipogenesis and the physiology of both white and brown adipose tissue. Furthermore, we highlight the critical role of key modulators, such as cytosolic aconitase, mitochondria, and macrophages, in maintaining iron homeostasis within adipose tissue.
Topics: Humans; Iron; Adipose Tissue; Adipose Tissue, Brown; Obesity; Insulin Resistance; Adipogenesis
PubMed: 37789591
DOI: 10.1111/obr.13647