Lineage tracing of PCs in developing and dystrophic muscle.

The progressive failure of muscle repair and an altered inflammatory response can lead to fibrosis that in turn can also negatively influence stem cells functionality (Nelson et al., 2012; Serrano and Munoz-Canoves, 2017).

While fibrosis typically begins as part of the wound healing response, excessive accumulation of collagen and other Extracellular Matrix (ECM) components during chronic injury/inflammation can lead to the destruction of normal tissue architecture and is thought to contribute to age-associated loss of tissue and organ decline (Serrano and Munoz-Canoves, 2017).

ESR5 will study their fate and the intrinsic/extrinsic mechanisms that regulate fate choices in developing and regenerating muscle. Understanding the nature of stem cells interaction in the niche is indeed an obligatory step toward new approaches in stem cell therapy (Cossu et al., 2018; De Luca et al., 2019; Galli et al., 2018).

ESR5 will use the Tg:TNAP-CRERT mouse (Dellavalle et al., 2011) or other CRERT mice (e.g. NG2-CRERT) (Roostalu et al., 2018) to perform in vivo lineage tracing analysis of pericytes (PC) and myoblasts (MB) during development, in mouse models of muscular dystrophy (Camps et al., 2020) and mice mutant for genes regulating fibrosis (e.g. TGF-β receptor) (Arno et al., 2019), both at different times of development, and during disease progression.

Moreover, ESR5 will study pPC and skeletal MB contribution to blood vessel wall formation, myofibres and fibrotic tissue. To visualize clonal progeny during development and pathology ESR5 will use various CreERT driver on a Rosa Confetti background (at low tamoxifen) to identify histochemically the composition of various clones (myogenic, smooth, fibrotic or endothelial). Finally, sorted populations will be challenged in vitro with different ECM proteins (e.g. laminins, collagens) and signaling molecules (e.g. Noggin, TGF β) to determine which of these molecules (and combination thereof) may promote one cell fate at the expense of the others.

Arno, B., Galli, F., Roostalu, U., Aldeiri, B.M., Miyake, T., Albertini, A., Bragg, L., Prehar, S., McDermott, J.C., Cartwright, E.J., et al. (2019). TNAP limits TGF-beta-dependent cardiac and skeletal muscle fibrosis by inactivating the SMAD2/3 transcription factors. J Cell Sci 132.
Camps, J., Breuls, N., Sifrim, A., Giarratana, N., Corvelyn, M., Danti, L., Grosemans, H., Vanuytven, S., Thiry, I., Belicchi, M., et al. (2020). Interstitial Cell Remodeling Promotes Aberrant Adipogenesis in Dystrophic Muscles. Cell Rep 31, 107597.
Cossu, G., Birchall, M., Brown, T., De Coppi, P., Culme-Seymour, E., Gibbon, S., Hitchcock, J., Mason, C., Montgomery, J., Morris, S., et al. (2018). Lancet Commission: Stem cells and regenerative medicine. Lancet 391, 883-910.
De Luca, M., Aiuti, A., Cossu, G., Parmar, M., Pellegrini, G., and Robey, P.G. (2019). Advances in stem cell research and therapeutic development. Nat Cell Biol 21, 801-811.
Dellavalle, A., Maroli, G., Covarello, D., Azzoni, E., Innocenzi, A., Perani, L., Antonini, S., Sambasivan, R., Brunelli, S., Tajbakhsh, S., et al. (2011). Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nat Commun 2, 499.
Galli, F., Bragg, L., Meggiolaro, L., Rossi, M., Caffarini, M., Naz, N., Santoleri, S., and Cossu, G. (2018). Gene and Cell Therapy for Muscular Dystrophies: Are We Getting There? Hum Gene Ther 29, 1098-1105.
Nelson, G., Wordsworth, J., Wang, C., Jurk, D., Lawless, C., Martin-Ruiz, C., and von Zglinicki, T. (2012). A senescent cell bystander effect: senescence-induced senescence. Aging cell 11, 345-349.
Roostalu, U., Aldeiri, B., Albertini, A., Humphreys, N., Simonsen-Jackson, M., Wong, J.K.F., and Cossu, G. (2018). Distinct Cellular Mechanisms Underlie Smooth Muscle Turnover in Vascular Development and Repair. Circ Res 122, 267-281.
Serrano, A.L., and Munoz-Canoves, P. (2017). Fibrosis development in early-onset muscular dystrophies: Mechanisms and translational implications. Semin Cell Dev Biol 64, 181-190.