Dynamic changes in transcription and epigenetic profile of fibro-adipogenic progenitors (FAPs) in healthy and dystrophic muscles, and modulation by epigenetic drugs (HDACi).
Muscle homeostasis relies on a population of muscle stem cells, the satellite cells (SCs), which support post-natal growth and are mainly responsible for skeletal muscle repair. It is well known that in addition to the canonical muscle stem cells, different cell types can in part influence either negatively or positively skeletal muscle homeostasis, including the macrophages, the resident fibro/adipogenic progenitors (FAPs) expressing platelet-derived growth-factor receptor (PDGFR)-α (Joe et al., 2010; Uezumi et al., 2011) and the PW1/Peg3 positive interstitial cells (myoPiCS) (Lewis et al., 2014; Pannerec et al., 2013).
We will focus on the non-satellite cell progenitors myoPICs, which display pronounced myogenic potential (Mitchell et al., 2010; Pannerec et al., 2013)but cannot compensate for the lack of SCs (Sambasivan et al., 2011). To further characterize these cells and discriminate myoPICs from other sub-populations, including PW1+/PDGFRα+ FAPs, ESR7 will use single cell transcriptomic analysis of FAPs isolated from WT and mdx mice (model of human DMD) as well as from DMD patients, exposed or not to HDACi, to isolate potential subpopulations of FAPs and define their gene expression profiles.
To characterise the transcriptome profiling and the epigenetic landscape in FAPs isolated from mdx mice, at different stages of disease progression and in response to treatment with HDAC inhibitors – a pharmacological intervention currently in clinical trial with DMD boys
- To identify distinct subpopulations of FAPs in muscles of mdx mice at different stages of disease progression and in response to treatment with HDAC inhibitors
To validate data generated in points 1 and 2 in FAPs isolated from muscles of DMD patients
Enrolment in Doctoral degree
Ph.D. Programme in Translational and Molecular Medicine (DIMET), University of Milano Bicocca (www.dimet.org).
Joe, A.W.B., Yi, L., Natarajan, A., Le Grand, F., So, L., Wang, J., Rudnicki, M.A., and Rossi, F.M.V. (2010). Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nature Cell Biology 12, 153-163.
Lewis, F.C., Henning, B.J., Marazzi, G., Sassoon, D., Ellison, G.M., and Nadal-Ginard, B. (2014). Porcine skeletal muscle-derived multipotent PW1pos/Pax7neg interstitial cells: isolation, characterization, and long-term culture. Stem cells translational medicine 3, 702-712.
Mitchell, K.J., Pannerec, A., Cadot, B., Parlakian, A., Besson, V., Gomes, E.R., Marazzi, G., and Sassoon, D.A. (2010). Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development. Nat Cell Biol 12, 257-266.
Pannerec, A., Formicola, L., Besson, V., Marazzi, G., and Sassoon, D.A. (2013). Defining skeletal muscle resident progenitors and their cell fate potentials. Development 140, 2879-2891.
Sambasivan, R., Yao, R., Kissenpfennig, A., Van Wittenberghe, L., Paldi, A., Gayraud-Morel, B., Guenou, H., Malissen, B., Tajbakhsh, S., and Galy, A. (2011). Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development (Cambridge, England) 138, 4333-4333.
Uezumi, A., Ito, T., Morikawa, D., Shimizu, N., Yoneda, T., Segawa, M., Yamaguchi, M., Ogawa, R., Matev, M.M., Miyagoe-Suzuki, Y., et al. (2011). Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. Journal of Cell Science 124, 3654-3664.