Stem Cell Environment and Skeletal Muscle Homeostasis

Stem cells are important in the maintenance and repair of many tissues all along the life span. It is the case in skeletal muscle, which presents high plasticity and regenerative properties. Normal skeletal muscle mobilizes tissue-associated endogenous stem cells, mainly satellite cells, and also upstream peri- endothelial stem cells, to repair damaged myofibres.

A key issue we address is the tissue environment in which muscle stem cells are activated. Environment plays important roles in the behavior of muscle stem cells and myogenic cells, although the mechanisms are poorly unknown. Various cell types in the vicinity of stem cells communicate with each other to correctly drive regeneration. We explore the roles of immune cells (inflammation), endothelial and peri-endothelial cells (angiogenesis) and interstitial cells (fibrosis) in both myogenic cell fate in normal healthy regenerating muscle and in the pathogenesis of muscular dystrophies. Indeed, degenerative myopathies are characterized by alteration in the environment of muscle stem cells, such as the presence of chronic inflammation and fibrosis, which are detrimental for both tissue repair and cell therapies.

Macrophages

Skeletal muscle regeneration is associated with the presence of macrophages. Two main inflammatory types of macrophages are present during skeletal muscle regeneration, which exert distinct effects on myogenic cells. Soon after injury, inflammatory monocytes enter into the damaged muscle and these inflammatory macrophages stimulate the proliferation of myogenic precursor cells. Later, they switch their phenotype into anti-inflammatory macrophages that sustain myogenic differentiation and myofibre growth. Macrophages can be considered as a stromal support for myogenic cells that helps the sequential steps of skeletal muscle regeneration and which use may be of interest to improve myogenic cell therapies.

Molecular mechanisms that control macrophage inflammatory states during skeletal muscle regeneration start to be understood, among which AMPK, the main energetic sensor in the cells, which controls the skewing towards the anti-inflammatory state. We also aim at identifying the cues secreted by macrophages that support myogenesis. We also investigate the roles and identity of macrophage populations during degenerative myopathies, during which the whole skeletal muscle homeostasis is unbalanced, and particularly the impact of macrophages on myogenesis and fibrosis in this pathological context.

Vessel cells

Whatever their status, satellite cells and myogenic precursor cells are close to capillaries. Endothelial and peri-endothelial cells develop specific interactions with myogenic cells. Endothelial cells and myogenic precursor cells interact to stimulate each other growth and differentiation. On the contrary peri-endothelial cells (smooth muscle cells) promote the self-renewal and maintain into quiescence of myogenic cells. A main regulator of these effects is the Angipoietin-1-Tie-2-ERK signaling pathway.

We aim at understanding the molecular regulation of the coupling between angiogenesis and myogenesis during skeletal muscle regeneration, as well as identifying whether these interactions are altered during degenerative and inflammatory myopathies.

Muscle stem cell homeostasis

Although extrinsic factors, coming from their environment, participate in the regulation of muscle stem cell fate, intrinsic molecular pathways also control this process. We are investigating the role of such factors, notably in the self-renewal of muscle stem cells. We aim at understanding whether those intrinsic factors may be altered by systemic changes such as metabolic alteration.

Our goal is to identify new functions for the cell neighbors of muscle stem cells beside their canonical properties (regulation of inflammation for macrophages, supply of oxygen and nutriments for vessel cells) and how muscle stem cells are controlled by their closest environment in both normal and pathological contexts. The identification of new molecules or novel functions of already known pathways are the basis for expanding our current understanding about skeletal muscle plasticity and its pathophysiology.