Macrophage-derived Spp1 promotes an adipogenic stromal cell population that contributes to intramuscular fat in dystrophic muscle
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE297956 | GEO | 2025/05/23
REPOSITORIES: GEO
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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: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
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 M-bM-^@M-^S 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 M-bM-^@M-^\HDAC-myomiR-BAF60 variant networkM-bM-^@M-^] 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 M-bM-^@M-^\latentM-bM-^@M-^] 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) 1.2, 133 and 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. Genome-wide chromatin accessibility patterns in FAPs cells derived from mdx mice at different ages treated either with HDAC inhibitor Trichostatin A (TSA) or with vehicle (saline solution) were assessed using NA-seq (PMID: 19289091)
2014-04-02 | E-GEOD-52062 | biostudies-arrayexpress
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) 1.2, 133 and 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.
2014-04-02 | GSE52062 | 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.
2014-04-23 | GSE51933 | GEO
Project description:Fibro-Adipogenic Progenitors (FAPs) are currently defined by their anatomical position, expression of non-specific membrane-associated proteins, ability to adopt multiple lineages and to perform different biological activities in response to physiological or pathological stimuli. Gene expression analysis at single cell level revealed the intrinsic heterogeneity of FAPs and uncovered discrete subpopulations (subFAPs), which can be prospectively isolated by FACS, based on the expression levels of Tie2 and Vcam1. Tie2-expressing (Tie2+) and Tie2/Vcam1 double negative (DN) subFAPs were present in unperturbed muscles and promptly expanded upon acute injury. By contrast, Vcam1-expressing subFAPs (Vcam1+) were undetectable in unperturbed muscles, but appeared “de novo” upon acute injury and expanded with a shifted kinetic compared to Tie2+ and DN FAPs. While Vcam1+ subFAPs were completely cleared upon resolution of muscle regeneration following acute injury, they persisted in chronically injured muscles from the mdx mouse model of Duchenne Muscular Dystrophy (DMD). “Nested” RNA-seq analysis of subFAPs revealed subpopulation-specific gene expression profiles that were dynamically regulated along the regeneration process, predicted specific biological activities and functional interactions with other cell types, and exhibited DMD-specific signatures. In particular, Vcam1+ subFAPs showed enrichment in fibrotic gene expression and myofibroblast markers, and their altered clearance in acutely injured muscles upon macrophage depletion was associated with fibrosis. These data reveal the individual contribution of distinct subFAPs to the physiological and pathological repair of skeletal muscles, thereby providing new insights into the pathogenesis of muscular dystrophies and targets for selective therapeutic interventions. RNA-seq study of bulk FAPs or subFAPs isolated by Fluorescence Activated Cell Sorting (FACS) from hind limb muscles of young (3 months old) mice. RNA-seq was performed in cells from wild type mice, either unperturbed (WT) or at 3 days post notexin-mediated intramuscular acute injury (WT-inj 3d). We also included dystrophic mice (MDX), the murine model of Duchenne Muscular Dystrophy (DMD) that provides an experimental setting for chronic muscle injury
2018-07-31 | GSE100474 | GEO
Project description:We investigated the transcriptome of cell states identified in fibro/adipogenic progenitors (FAPs) isolated from mdx mice using as a criterion SCA-1 expression. We found that after 5 days in growth medium FAP cell states have different transcriptomes. In particular, among the "Biological process" GO terms enriched in genes up-regulated in SCA1-High-FAPs we found genes correlated with adipogenic differentiation. Indeed, several genes directly regulated by PPAR-gamma are up-regulated in SCA1-High-FAPs. This experiment demonstrates that the adipogenic propensity of SCA1-High-FAPs arise spontaneously in vitro.
2020-12-11 | GSE163016 | GEO
Project description:Utilizing glycerol intramuscular injections in M. musculus provides a model of skeletal muscle damage followed by skeletal muscle regeneration. In particular, glycerol-induced muscle injury triggers accute activation of muscle Fibro/Adipogenic Progenitors, also called FAPs. However, aging dramatically impairs FAP function. We characterized genome-wide expression profiles of young and old FAPs in the non-proliferative and activated state, freshly isolated to non-injured or damaged muscles, respectively. Our goal was to uncover new regulatory signalings specific to FAP entry into the activation program that are affected with age.
2018-11-26 | GSE92508 | GEO
Project description:Wagyu cattle are renowned for their premium beef characterized by abundant intramuscular fat (IMF). In contrast, Brahman, a popular breed in the southern coastal area of the US, generally produces tough meat with scarce IMF. However, the mechanisms underlying the differential meat quality between the two breeds are still largely unknown. Using single-cell RNAseq (scRNAseq), we identified many tissue-resident and immune cell types in Wagyu, Brahman, and Wagyu/Brahman crossbred cattle muscle. Multiple fibro/adipogenic progenitor (FAP) subpopulations were identified, including an endomysial adipogenic subpopulation and a perimysial fibrogenic subpopulation. Further analysis comparing individual FAP subpopulations between Wagyu and Brahman identified stronger pro-adipogenic gene expression in Wagyu adipogenic FAP subpopulation and higher pro-fibrogenic gene expression in Brahman fibrogenic FAP subpopulation. Overexpression of CFD, a gene upregulated in Wagyu adipogenic FAPs, enhanced the adipogenic efficiency of FAPs. Moreover, the expression of CFD in FAPs was positively correlated with the IMF content. Interestingly, the expression of CFD was identified in human FAPs but not FAPs of mouse models of intramuscular adipogenesis, suggesting that CFD is a species-specific regulator of IMF formation. Using a mouse line that allows lineage-tracing of FAPs expressing Postn, a gene upregulated in Brahman FAPs, we found that Postn expression was specifically activated during fibrogenic but not adipogenic programming. Cell-cell communication analysis revealed robust interactions between FAPs and other cell types, further suggesting the critical role of FAPs in bovine skeletal muscle growth, development, and homeostasis.
2023-07-01 | GSE205347 | GEO
Project description:Pharmacological treatment of Duchenne Muscular Dystrophy (DMD) with histone deacetylase inhibitors (HDACi) is currently being tested in clinical trials. Pre-clinical studies performed in mdx mice - the mouse model of DMD - have shown that HDACi promote compensatory muscle regeneration, while inhibiting fibro-adipogenic degeneration, by targeting fibro-adipogenic progenitors (FAPs); however, these beneficial effects are restricted to early stages of disease progression. We show here that FAPs from late stage mdx mice exhibit epigenetic and transcriptional features of senescence that could not be fully reversed by HDACi. In particular, genome-wide increase in H3K9/14 acetylation at gene promoters of Senescence Associated Secretory Phenotype (SASP) genes was associated with their upregulation in late stage mdx FAPs. Treatment with the HDACi Trichostatin A (TSA) could inhibit SASP gene activation in FAPs, by decreasing H3K9/14 acetylation. Conversely, combinatorial decrease of H3K27 and/or H3K9/14 acetylation at promoters of genes required for cycle activation and progression was associated with their downregulation in FAPs from late stage mdx mice. However, these epigenetic and transcriptional alterations could not be reversed by TSA, due to a general resistance exhibited by FAPs from late stage mdx mice to HDACi-induced H3K9/14 hyperacetylation. Overall, this data reveal that disease-associated features of senescence develop in FAPs of DMD muscle through epigenetically distinct and pharmacologically dissociable events, and suggests that HDACi might at least retain anti- fibrotic and inflammatory activity at late stages of DMD, by repressing FAP-derived SASP.
2022-02-01 | GSE189824 | GEO