Unknown,Transcriptomics,Genomics,Proteomics

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Gene profile of dystrophic cardiac progenitor cells

ABSTRACT: Cardiac resident stem/progenitor cells are intensively studied as a potential therapeutic tool for cardiomyopathies. While surface marker expression and ability to generate cardiomyocytes have been characterized in some detail for several types of these progenitors, little is known on how their cardiac differentiation is regulated. Beta sarcoglycan null (bSG KO) mice are a model for limb girdle muscular dystrophy type 2E (LGMD2E), and are characterized by muscular dystrophy and progressive dilated cardiomyopathy. In the present study we isolated and characterized cardiac progenitors (mesoangioblasts) from the small vessels of neonatal hearts bSG KO mice and unexpectedly observed that they differentiate spontaneously into skeletal muscle fibers both in vitro and when transplanted in regenerating muscles and infarcted hearts. The micro array data showed that dystrophic cardiac progenitor and myogenic cells (C2C12) share similar gene expression profile. Keywords: Beta sarcoglycan null mice, muscular dystrophy, cardiac mesoangioblasts, myogenic differentiation Biological triplicates of cardiac wild-type and dystrophic mesoangioblasts isolated from different heart region (atrium, ventricle, aorta) were compared. C2C12 cells were used as positive control for myogenic differentiation.

ORGANISM(S): Mus musculus

SUBMITTER: Joke Allemeersch

PROVIDER: E-GEOD-17774 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

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Gene profile of dystrophic cardiac progenitor cells

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