Muscle Regeneration

Fibroadipogenic progenitors (FAPs) and skeletal muscle regeneration

Skeletal muscles are capable of regenerating after damage. This is possible owing not only to myogenic stem cells (MSCs), from which new myofibers originate, but also to several non-myogenic cell types resident in muscles. Among these, fibro-adipogenic progenitors (FAPs) are known progenitors of tissue-fibroblasts/myofibroblasts and adipocytes. FAPs, are quiescent in healthy muscles, but are triggered to proliferate in situation of muscle damage, resulting in a transient fibrosis, during which they positively influence the myogenic repair process [1, 2]. Besides secreting pro-myogenic factors, FAP activation/expansion enables the transient production of extracellular matrix (ECM), which provides the adequate tissue-stiffness for MSCs to undergo myogenic differentiation [3, 4].

Given their differentiation potential, FAP expansion and differentiation are strictly suppressed in healthy muscles, and strongly limited in situation of skeletal muscle repair, to prevent the appearance of fibrosis and adipose infiltrates, two adverse events occurring in pathological contexts. A first gatekeeper drastically limits their differentiation, while a second mechanism ensures the elimination of activated FAPs present in excess by the innate immune system, prior to the phase of extensive growth of the newly generated fibres [5, 6].

Little is known on the mechanisms suppressing FAP differentiation in time and space. Interestingly, fibrosis and adipose infiltrations (products of FAP differentiation) are symptoms common to several muscular dystrophies [7, 8]. Thus, irrespective of their respective genetic cause, these pathological contexts lead to unleashed FAP differentiation and defective elimination. Preventing fibrosis has become a major goal in the field of muscle pathologies, with emphasis on inhibition of the TGFβ pathway as the leading known fibrosis inducer. To this aim, a key unmet need is to identify naturally occurring mechanisms that block fibro-adipogenic differentiation in healthy muscles, and to understand what is altered in pathological contexts.

Recently, we have identified a novel regulator of intramuscular fibro-adipogenic differentiation, representing a key starting point to shed some light on this process. We now aim to identify modulators of fibro-adipogenic differentiation necessary to ensure FAP homeostasis. Taking advantage of several murine models of muscular dystrophies with deregulated FAP homeostasis (DFH) leading to fibrosis and adipose infiltrations, we propose a comprehensive program aiming to identify signals deregulated in DHF models accounting for unleashed fibro-adipogenic differentiation, and to distinguish the most promising therapeutic targets

References:

  1. Uezumi, A., et al. Nat Cell Biol, 2010. 12(2): p. 143-52.
  2. Joe, A.W., et al. Nat Cell Biol, 2010. 12(2): p. 153-63.
  3. Lukjanenko, L., et al. Cell Stem Cell, 2019.
  4. Biferali, B., et al. Front Physiol, 2019. 10: p. 1074.
  5. Lemos, D.R., et al. Nat Med, 2015. 21(7): p. 786-94.
  6. Heredia, J.E., et al. Cell, 2013. 153(2): p. 376-88.
  7. Contreras, O., et al. Cell Tissue Res, 2016. 364(3): p. 647-60.
  8. Mozzetta, C., et al. EMBO Mol Med, 2013. 5(4): p. 626-39.