The FibromiR miR-214-3p is upregulated in fibrotic Duchenne Muscular Dystrophy and promotes differentiation of Fibro-Adipogenic muscle progenitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA662364 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12610818.fastq.gz | Fastqsanger.gz | |||
| SRR12610819.fastq.gz | Fastqsanger.gz | |||
| SRR12610820.fastq.gz | Fastqsanger.gz | |||
| SRR12610821.fastq.gz | Fastqsanger.gz | |||
| SRR12610822.fastq.gz | Fastqsanger.gz |
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Project description:Fibrosis is a deleterious invasion of tissues associated with many pathological conditions, such as Duchenne muscular dystrophy (DMD) for which no cure is at present available for its prevention or its treatment. Fibro-adipogenic progenitors (FAPs) are resident cells in the human skeletal muscle and can differentiate into myofibroblasts, which represent the key cell population responsible for fibrosis. In this study, we delineated the pool of microRNAs (miRNAs) that are specifically modulated by TGFβ1 in FAPs versus myogenic progenitors (MPs) by a global miRNome analysis. A subset of candidates, including several "FibromiRs", was found differentially expressed between FAPs and MPs and was also deregulated in DMD versus healthy biopsies. Among them, the expression of the TGFβ1-induced miR-199a~214 cluster was strongly correlated with the fibrotic score in DMD biopsies. Loss-of-function experiments in FAPs indicated that a miR-214-3p inhibitor efficiently blocked expression of fibrogenic markers in both basal conditions and following TGFβ1 stimulation. We found that FGFR1 is a functional target of miR-214-3p, preventing the signaling of the anti-fibrotic FGF2 pathway during FAP fibrogenesis. Overall, our work demonstrates that the « FibromiR » miR-214-3p is a key activator of FAP fibrogenesis by modulating the FGF2/FGFR1/TGFβ axis, opening new avenues for the treatment of DMD.
| S-EPMC8303294 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-08-30 | GSE157675 | 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
Project description:Fibrosis is a prominent pathological feature of skeletal muscle in Duchenne muscular dystrophy (DMD). The commonly used disease mouse model, mdx5cv, displays progressive fibrosis in diaphragm but not limb muscles. We use single-cell RNA sequencing to determine the cellular expression of the genes involved in extracellular matrix (ECM) production and degradation in mdx5cv diaphragm and quadriceps. We find that fibro/adipogenic progenitors (FAPs) are not only the primary source of ECM but also the predominant cells that express important ECM regulatory genes, including Ccn2, Ltbp4, Mmp2, Mmp14, Timp1, Timp2, and Loxs. The effector and regulatory functions are exerted by diverse FAP clusters which are different between diaphragm and quadriceps, indicating their activation by different tissue microenvironment. FAPs are more abundant in diaphragm than in quadriceps.
2023-01-03 | GSE218201 | GEO
Project description:Fibrosis is a deleterious invasion of tissues associated with many pathological conditions, such as Duchenne muscular dystrophy (DMD) for which no cure is at present available for its prevention or its treatment. Fibro-adipogenic progenitors (FAPs) are resident cells in the human skeletal muscle and can differentiate into myofibroblasts, which represent the key cell population responsible for fibrosis. In this study, we delineated the pool of microRNAs (miRNAs) that are specifically modulated by TGFβ1 in FAPs versus myogenic progenitors (MPs) by a global miRNome analysis. A subset of candidates, including several "FibromiRs", was found differentially expressed between FAPs and MPs and was also deregulated in DMD versus healthy biopsies. Among them, the expression of the TGFβ1-induced miR-199a~214 cluster was strongly correlated with the fibrotic score in DMD biopsies. Loss-of-function experiments in FAPs indicated that a miR-214-3p inhibitor efficiently blocked expression of fibrogenic markers in both basal conditions and following TGFβ1 stimulation. We found that FGFR1 is a functional target of miR-214-3p, preventing the signaling of the anti-fibrotic FGF2 pathway during FAP fibrogenesis. Overall, our work demonstrates that the « FibromiR » miR-214-3p is a key activator of FAP fibrogenesis by modulating the FGF2/FGFR1/TGFβ axis, opening new avenues for the treatment of DMD.
2021-08-30 | GSE157674 | 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:We used single cell RNA-sequencing analysis to analyze the transcriptomic heterogeneity of fibro-adipogenic progenitors in skeletal muscle
2023-11-23 | GSE247415 | GEO
Project description:Skeletal muscle wasting results from numerous pathological conditions impacting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss of function models combined with in vivo cell biology and proteomic approaches, we identified the endoplasmic reticulum chaperone, BiP, as a novel target of the E3 ubiquitin ligase atrogin-1. A loss in atrogin-1 results in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fibre integrity. We further implicate a disruption in atrogin-1 mediated BiP regulation in the pathogenesis of Duchenne Muscular Dystrophy. We reveal that BiP is not only upregulated in Duchenne Muscular Dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorates pathology in a zebrafish model of Duchenne Muscular Dystrophy. Collectively, our data implicates a novel disease axis in the pathogenesis of Duchenne Muscular Dystrophy, and highlights atrogin-1’s essential role in maintaining muscle homeostasis.
2024-03-07 | PXD038406 | Pride
Project description:Loss of motoneuron innervation (denervation) is a hallmark of neurodegeneration and aging of the skeletal muscle. Denervation induces fibrosis, a response attributed to the activation and expansion of resident fibro/adipogenic progenitors (FAPs), i.e., multipotent stromal cells with myofibroblast potential. Using in vivo and in silico approaches, we revealed FAPs as a novel cell population that activates the transcriptional coregulators YAP/TAZ in response to skeletal muscle denervation. Here, we found that denervation induces the expression and transcriptional activity of YAP/TAZ in whole muscle lysates. Using the PdgfraH2B:EGFP/+ transgenic reporter mice to trace FAPs, we demonstrated that denervation leads to increased YAP expression that accumulates within FAPs nuclei. Consistently, re-analysis of published single-nucleus RNA sequencing (snRNA-seq) data indicates that FAPs from denervated muscles have a higher YAP/TAZ signature level than control FAPs. Thus, our work provides the foundations to address the functional role of YAP/TAZ in FAPs in a neurogenic pathological context, which could be applied to develop novel therapeutic approaches for the treatment of muscle disorders triggered by motoneuron degeneration.
| S-EPMC10059792 | biostudies-literature
Project description:Genetic Modifiers of Duchenne Muscular Dystrophy
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