Integration of signaling pathways controlling muscle fibrosis – Myo-Fibrosis

The Myo-Fibrosis project proposes to unravel the complexity of the distinct cell subpopulations involved in fibrosis (using unbiased single cell approaches) and the signaling pathways controlling fibrosis (using a series of genetically modified cells in vivo and ex vivo). The elucidation of an integrated and comprehensive framework of the cellular events underlying the steps of muscle fibrosis represents crucial missing information, which will undoubtedly push forward the frontier of our current knowledge on fibrogenesis. Because fibrosis is the major obstacle for cell and gene therapy approaches that are proposed, understanding the mechanisms controlling fibrosis is of paramount importance to open promising therapeutic avenues for muscular dystrophies.

Our analysis of the fibroadipogenic behavior and functions is ongoing.

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Muscular dystrophies, such as Duchenne muscular dystrophy (DMD), are characterized by dysfunction of myofibers and increase in the collagenous endomysial tissue, known as fibrosis. Because the primary defect targets myofibers and myogenic cells, previous work has been almost exclusively focused on muscle stem cells (MuSCs). Moreover, fibrosis has been regarded as a compensatory response to muscle damaging. However, more recent studies have shown that increased fibrosis is predictive of higher muscle damage and earlier muscle function loss in DMD patients.
In regenerating skeletal muscle, myogenesis is operated by MuSCs and is sustained by tightly coordinated environmental neighborhood, including inflammatory cells, vascular cells and fibro-adipogenic progenitors (FAPs). FAPs are mesenchymal fibroblastic cells located in the interstitial space between the muscle fibers. During muscle regeneration, FAP homeostasis is tightly regulated by pro-inflammatory and anti-inflammatory macrophages. Once the muscle is repaired, FAPs return to quiescence. Instead, in pathological contexts, as in DMD, FAPs proliferate and differentiate leading to increased fibrosis and fat infiltrations. Although FAPs are the main cells responsible for fibrosis in degenerative myopathies, the molecular pathways regulating their fate and functions are not known.
Despite the importance of this process, the mechanisms by which fibrogenesis takes place and is molecularly controlled have been overlooked. This lack of knowledge may be due both to the complexity exhibited by the immune system in a chronic situation and to the lack of markers to properly identify and characterize both immune and fibroblastic cells. Thanks to the recent data generated by the teams of the Consortium, specific cell populations (fibroblastic and immune cells) have been identified in the dystrophic context, allowing to investigate their function in fibrogenesis. Moreover, they identified several signaling pathways that are activated in FAPs, notably in a myopathic context, and their control by inflammatory cells, which constitutes a new and major focus in the study of degenerative myopathies. Interestingly, pharmacological targeting of some of these pathways was shown to decrease fibrosis in DMD mice, highlighting the relevance of FAP signaling pathways in fibrosis establishment in degenerative myopathies.
Overall the consortium data allow proposing the following hypothesis: in dystrophic muscle, new crosstalks are established between activated MuSCs, macrophages and FAPs that involve paracrine and cell-to-cell signaling pathways to promote fibrosis.
The Myo-Fibrosis project proposes to unravel the complexity of the distinct cell subpopulations involved in fibrosis (using unbiased single cell approaches) and the signaling pathways controlling fibrosis (using a series of genetically modified cells in vivo and ex vivo). The elucidation of an integrated and comprehensive framework of the cellular events underlying the steps of muscle fibrosis represents crucial missing information, which will undoubtedly push forward the frontier of our current knowledge on fibrogenesis. Because fibrosis is the major obstacle for cell and gene therapy approaches that are proposed, understanding the mechanisms controlling fibrosis is of paramount importance to open promising therapeutic avenues for muscular dystrophies.