The effects of TGFBR3 on adipogenesis of FAPs
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE283671 | GEO | 2025/11/01
REPOSITORIES: GEO
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Project description:Platelet-rich plasma (PRP) is used to treat musculoskeletal diseases, such as rotator cuff tears, and has been proven to attenuate fatty infiltration in muscle injury; however, the effective components are still unclear. In this study, we found that young donor-derived exosomes were critical components in PRP that regulate fatty infiltration in muscle injury by directly inhibiting adipogenesis of muscle-resident FAPs.
2025-11-01 | GSE284069 | GEO
Project description:Fatty infiltration, the ectopic deposition of adipose tissue within skeletal muscle, is mediated via the adipogenic differentiation of fibro-adipogenic progenitors (FAPs). We used single-nuclei and single-cell RNA sequencing to characterize FAP heterogeneity in patients with fatty infiltration. We identified an MME+ FAP subpopulation which, based on ex vivo characterization as well as transplantation experiments, exhibits high adipogenic potential. MME+ FAPs are characterized by low activity of WNT, known to control adipogenic commitment, and are refractory to the inhibitory role of WNT activators. Using preclinical models for muscle damage versus fatty infiltration, we show that many MME+ FAPs undergo apoptosis during muscle regeneration and differentiate into adipocytes under pathological conditions, leading to their depletion. Finally, we utilized the varying fat infiltration levels in human hip muscles to show the depletion of MME+ FAPs in fatty infiltrated human muscle. Altogether, we have identified the dominant adipogenic FAP subpopulation in skeletal muscle.
2023-01-18 | GSE200487 | GEO
Project description:Injured skeletal muscle regenerates, but with age or in muscular dystrophies, muscle is replaced by fat. Upon injury, muscle-resident fibro/adipogenic progenitors (FAPs) proliferated and gave rise to adipocytes. These FAPs dynamically produced primary cilia, structures that transduce intercellular cues such as Hedgehog (Hh) signals. Genetically removing cilia from FAPs inhibited intramuscular adipogenesis, both after injury and in a mouse model of Duchenne muscular dystrophy. Blocking FAP ciliation also enhanced myofiber regeneration after injury and reduced myofiber size decline in the muscular dystrophy model. Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes, pointing to a strategy to combat fatty degeneration of skeletal muscle. We conclude that ciliary Hh signaling by FAPs orchestrates the regenerative response to skeletal muscle injury.
2017-07-13 | GSE86073 | GEO
Project description:The purpose of this study is to investigate how melatonin-influenced promyogenic factor secreted from fibro-adipogenic progenitors (FAPs) regulate muscle regeneration and muscle cell fusion during muscle repair. We highlighted the role of melatonin in regulating crosstalk between muscle stem cells and FAPs during muscle regeneration. Mice that were treated with melatonin exhibited improved muscle regeneration and reduced intramuscular fat deposition, which were associated with enhanced myogenesis, remodeled lipid metabolism and reduced immune cell infiltration. Notably, melatonin did not exert positive effects on cell fusion and myotube formation during differentiation. Interestingly, melatonin repressed fibro-adipogenic progenitor (FAP) adipogenesis in a dose-dependent manner in vitro. Furthermore, melatonin treatment enhanced the pro-myogenic effects of FAPs, which stimulated GDF10 secretion to promote muscle cell fusion and induce myotube hypertrophy.
2023-06-30 | GSE214008 | GEO
Project description:In human dystrophies, the progressive muscle wasting is exacerbated by ectopic deposition of fat and fibrous tissue originating from fibro/adipogenic progenitors (FAPs). In degenerating muscles, the ability of these cells to adjuvate a successful healing is attenuated and FAPs aberrantly expand and differentiate into adipocytes and fibroblasts. Thus, arresting the fibroadipogenic fate of FAPs, without affecting their physiological role, represents a valuable therapeutic strategy for patients affected by muscle diseases. Here, using a panel of adipose progenitor cells including human-derived FAPs coupled with pharmacological perturbations and proteome profiling, we report that LY2090314 interferes with a genuine adipogenic program acting as WNT surrogate for the stabilization of a competent -catenin transcriptional complex. To predict the beneficial impact of LY2090314 in limiting ectopic deposition of fat in human muscles, we combined the Poly-Ethylene-Glycol-Fibrinogen biomimetic matrix with these progenitor cells to create a miniaturized 3D model of adipogenesis. Using this scalable system, we demonstrated that a two-digit nanomolar dose of this compound is effective to repress adipogenesis in a higher 3D scale, thus offering a concrete proof for the use of LY2090314 to limit FAP-derived fat infiltrates in dystrophic muscles.
2023-06-13 | PXD040479 | Pride
Project description:We detected and compared the miRNAs contained in Y-PRP-exos or O-PRP-exos. The results showed that most miRNAs (38) can be identified in both Y-PRP-exos and O-PRP-exos. In addition, hsa-let-7f-5p, hsa-miR-16-5p and hsa-miR-126-3p were top 3 enriched miRNAs in PRP-exos of all donors. These results indicated the heterogeneity of miRNAs in PRP-exos was small, regardless of age. However, the abundance of miRNAs in Y-PRP-exos and O-PRP-exos was quite different, especially in high-ranking miRNAs. The expression of hsa-miR-16-5p and has-let-7f-5p in O-PRP-exos in two old donors was only approximately 1/4-1/2 of that in Y-PRP-exos in two young donors
2023-11-30 | GSE234781 | GEO
Project description:Fibro adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin- deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild type and mdx mice, suggest that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.
2019-06-24 | PXD014195 | Pride
Project description:Facial infiltrating lipomatosis (FIL) is a congenital disorder characterized by unilateral facial enlargement. Although next-generation sequencing has revealed that the pathogenesis of FIL is associated with phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations, the underlying molecular mechanisms remain undetermined. We found that the adipose tissue in FIL patients demonstrated tissue infiltration accompanied by adipocytes hypertrophy and increased lipid accumulation. All FIL derived fibro-adipose progenitor cells (FIL-FAPs) harboured PIK3CA mutations. Compared to FAPs obtained from normal subcutaneous adipose tissue, FIL-FAPs exhibited a greater capacity for adipogenesis. Suppression of PIK3CA resulted in a reduction in the adipogenic potential of FIL-FAPs. Through single cell sequencing, we find that FIL-FAPs had higher expression of FKBP5. Inhibiting FKBP5 can impair the adipogenic capacity of FIL-FAPs. We also verified that PI3K-AKT pathway regulating FKBP5 expression. To find the downstream target of FKBP5, we performed RNA-seq of FIL-FAPs treated with FKBP5 inhibitor SAFit2 in DMSO or DMSO alone.
2025-08-08 | GSE279487 | GEO
Project description:Skeletal muscle regeneration is primarily accomplished through the concerted action of the myoblasts as well as the supporting stromal cells. Following accomplishment of injury repair, activated stromal cells disappear via apoptosis. In the case of muscle dystrophies where in a chronic inflammatory environment is present, activated stromal cells are transformed into a myofibroblastic state with the deposition of extracellular matrix components. Excessive accumulation of ECM leads to irreversible fibrosis and tissue deterioration. A distinct stromal cell population named fibro-adipogenic precursors (FAPs) are known to be responsible for contribution to fibrosis and fatty infiltration. Fibrosis is also evident in disuse atrophy and sarcopenia without any significant inflammation. This study aims to analyze the heterogeneous population of FAPs comparatively in the course of acute damage and immobilization models. We isolated and analyzed the mononuclear cell population of skeletal muscles following tenotomy and denervation models in mice. Immunophenotyping of the FAPs was conducted based on exclusion of CD45, CD31 and CD11b and a comparative analysis was accomplished on three different subpopulations of i) CD140a(+), Sca1(+) ii) CD140a(+), Sca1(-) iii) CD140a(-), Sca1(+). High-throughput transcriptome analysis was employed to further characterize the transcriptome of these three cell populations and compare their quiescent and activated states. Results: Investigated sub-populations exhibited diverse activation properties and kinetics for each studied model. While CD140a(+), Sca1(+) was the predominating activated population along with tenotomy, denervation majorly stimulated the proliferation of CD140a(+), Sca1(+) cells. Both immobilization models lacked myofiber damage and exhibited a minute inflammatory response compared to the acute damage. Transcriptome analysis supports commonalities in upregulation of ECM components in diverse subpopulation of cells as well as discriminating candidate cell surface markers. Skeletal muscle regeneration is primarily accomplished through the concerted action of the myoblasts as well as the supporting stromal cells. Following accomplishment of injury repair, activated stromal cells disappear via apoptosis. In the case of muscle dystrophies where in a chronic inflammatory environment is present, activated stromal cells are transformed into a myofibroblastic state with the deposition of extracellular matrix components. Excessive accumulation of ECM leads to irreversible fibrosis and tissue deterioration. A distinct stromal cell population named fibro-adipogenic precursors (FAPs) are known to be responsible for contribution to fibrosis and fatty infiltration. Fibrosis is also evident in disuse atrophy and sarcopenia without any significant inflammation. This study aims to analyze the heterogeneous population of FAPs comparatively in the course of acute damage and immobilization models. We isolated and analyzed the mononuclear cell population of skeletal muscles following tenotomy and denervation models in mice. Immunophenotyping of the FAPs was conducted based on exclusion of CD45, CD31 and CD11b and a comparative analysis was accomplished on three different subpopulations of i) CD140a(+), Sca1(+) ii) CD140a(+), Sca1(-) iii) CD140a(-), Sca1(+). High-throughput transcriptome analysis was employed to further characterize the transcriptome of these three cell populations and compare their quiescent and activated states. Results: Investigated sub-populations exhibited diverse activation properties and kinetics for each studied model. While CD140a(+), Sca1(+) was the predominating activated population along with tenotomy, denervation majorly stimulated the proliferation of CD140a(+), Sca1(+) cells. Both immobilization models lacked myofiber damage and exhibited a minute inflammatory response compared to the acute damage. Transcriptome analysis supports commonalities in upregulation of ECM components in diverse subpopulation of cells as well as discriminating candidate cell surface markers.
2023-01-02 | GSE169411 | GEO
Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration - is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an "HDAC-myomiR-BAF60 variant network" regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) miR-1.2, miR-133 and miR-206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. miRNA modulation upon Histone Deacetylase inhibition in Fibro-Adipogenic Progenitors (FAPs) derived from young mdx mice was evaluated by small RNA-sequencing in 2 controls and 2 treated samples
2014-04-23 | E-GEOD-51933 | biostudies-arrayexpress