Single-cell RNA-seq of Fibroadipogenic progenitors from WT and Dysferlin KO mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE182293 | GEO | 2022/12/31
REPOSITORIES: GEO
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Project description:Fibrodysplasia ossificans progressiva (FOP) is a ultra rare disease causing the formation of extraskeletal bone in skeletal muscles and joint areas of affected patients, leading to progressive invalidation. To model the disease, we used the inducible Acvr1R206HloxP/loxP:CreERT2 mouse model. This study aims at investigating the early events occurring in FOP muscles, with a focus on unraveling if and how the interactions between macrophages and fibroadipogenic progenitors (FAPs) drive the formation of ectopic bone.
2026-07-06 | GSE302734 | GEO
Project description:Patients surviving stroke usually experience rapid muscle wasting and an increased risk of physical disability. Although multifactorial interactions including malnutrition, disuse, systemic catabolic imbalance and neurohormonal dysregulation are considered to contribute to the progression of stroke-related sarcopenia, the underlying mechanisms of this brain-muscle crosstalk remain elusive. Muscle-resident fibro/adipogenic progenitors (FAPs) are indispensable for maintaining muscle homeostasis and function as initial sensors of external perturbations. In the present study, we illustrate that FAPs rapidly respond to the overactive sympathetic nervous system (SNS), and egress from the muscle niche into circulation during the acute phase of stroke. In our study, we performed comparative transcriptomic analysis of circulating fibroadipogenic progenitors and muscle resident fibroadipogenic progenitors.
2025-07-31 | GSE272033 | 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 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:Muscle fibroadipogenic progenitor (FAP) cells, which are muscular mesenchymal cells that originate from lateral plate mesoderm have been proposed to act as a critical regulator for adult muscle homeostasis1–7, including the maturation and proper functioning of the neuromuscular junction (NMJ)3, Prx-Bap1 paper. However, the mechanism and intercellular crosstalk by which FAPs regulate the stability and functionality of neuromuscular system remains unknown. Here we show that FAPs not only locally but also systemically regulate the neuromuscular system through the secretion of a serine-type endopeptidase Granzyme E which may imply the previously unidentified endocrine function of FAPs. Local transplantation of wild-type FAPs into the neuromuscular disease model (Prrx1Cre;Bap1f/f, hereafter, cKO) can readily prevent neuromuscular defects, including degeneration of the neuromuscular junction and loss of motor neurons. These effects are found not only in transplanted hindlimb muscles but also in the contralateral hindlimb and even forelimb muscles. Notably, subcutaneous administration of microparticles encapsulating FAP-conditioned media into cKO mice was sufficient to restore normal neuromuscular functions. By analyzing the transcriptomic and secretomic profiles of FAPs, we identified a novel protein, Granzyme E, which is specifically expressed in and secreted by FAPs, and which indispensably regulates the structure and function of NMJ and motor neuron survival. Our study has defined a unique mechanism of Granzyme E-dependent, systemic control of the neuromuscular system by FAPs, which would provide a comprehensive understanding on the neuromuscular systems and their crosstalk with non-neuronal cells. These findings may provide a therapeutic benefit to treat NMJ-related diseases.
2022-08-31 | GSE199660 | GEO
Project description:Single-cell RNA-seq of Fibroadipogenic progenitors from WT and Dysferlin KO mice
| PRJNA755703 | ENA
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: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:Aging is associated with delayed skeletal muscle repair and regeneration. Loss of innervation occurs after degenerative muscle injury, however, the extent of denervation, whether the kinetics of reinnervation changes with aging, and the cellular consequences of neuromuscular junction (NMJ) disruption in adult and aged muscle have not been explored. Here we show after degenerative muscle injury progressive denervation and delayed reinnervation in aged compared to adult muscle. Using confocal microscopy and 3-D image rendering we found a relationship between innervation and myofiber size in aged regenerating muscle. Although timely inhibition of pro-inflammatory Ccr2 activity after degenerative muscle injury improved aged regenerated myofiber size, this was not associated with an increase in reinnervation. In contrast, single cell RNA sequencing (scRNASeq) analysis revealed denervation triggers an inflammatory response in target muscles regardless of age; however, pro-inflammatory signaling predominated in aged macrophages and fibroadipogenic progenitors (FAPs) compared to a pro-regenerative response in adult cells. Thus, denervation and delayed reinnervation of NMJs after injury is a feature of persistent pro-inflammatory signals associated with delayed repair and regeneration of aged muscle.
2022-06-05 | GSE205395 | 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:Fibroadipogenic progenitors (FAPs) play a key role in skeletal muscle homeostasis and regeneration. They produce extracellular matrix components and secrete cytokines that regulate muscle stem cell function. The number of FAPs and their activity need to be dynamically regulated to avoid their chronic accumulation and overproduction of fibrosis. However, the intrinsic factors by which FAPs control their cell fate decisions remain elusive. Here, we show that FAPs-secreted prostaglandin-E2 (PGE2) functions as a key autoregulatory factor. Using single cell lipidomics and single cell transcriptomics, we show that FAPs are the main cellular source of PGE2 in resting muscle and during regeneration. FAP-secreted PGE2 exerts paracrine effects that maintain the muscle stem cell pool at steady state and stimulate their proliferation post-injury. Moreover, it has autocrine effects that influence FAP fate decisions and promote their apoptosis. Administration of non-steroidal anti-inflammatory drugs that inhibit the prostaglandin-synthesizing enzyme COX2 increases FAPs content post-injury. Using Pdgfrα-CreERT2_Cox2flox mice, we showed that conditional ablation of COX2 specifically in FAPs increases FAPs content, fibrosis, and impairs muscle regeneration, which can be rescued by PGE2 administration. Furthermore, we show that PGE2 production in FAPs is impaired in mouse models of Duchenne muscular dystrophy, and we provide a proof-of-concept that PGE2 administration can reduce FAPs numbers, fibrosis accumulation, and increase muscle strength. Overall, we uncover a novel role for PGE2 beyond its function in inflammation and identify a mechanism by which FAPs intrinsically regulate their own cell fate, revealing therapeutic potential for muscle injury and dystrophic conditions.
2026-06-05 | GSE320353 | GEO