ESR4
Fibrogenic progenitors in skeletal muscle.
Pompeu Fabra University (UPF)
Description
Several studies support the emerging concept that inflammation controls stem cell fate/behaviour coordinating tissue repair (Munoz-Canoves and Serrano, 2015; Tidball and Villalta, 2010) and this balance is probably skewed in patients with late phases of chronic diseases, like muscle dystrophies and in aging (Leung and Wagner, 2013; Serrano and Munoz-Canoves, 2017) .
We will focus on how the inflammatory and vascular components integrate to coordinate muscle regeneration and how fibrosis develops in pathological conditions. We will study Endothelial-to-Mesenchymal-Transition (EndoMT) in chronic disease (on a mdx background) and in aging. ESR4 will study EndoMT in chronic disease (on a mdx background) and in aging by using the Cdh5-CreERT2:R26R-EYFP mice.
EYFP+ cells will be characterized for the expression of markers of ECs (e.g Ve-Cad and CD31), fibroblast (e.g. TCF4 and collagen) and other fibrogenic precursors (PDGFR-α, TNAP) while monitoring the progress of the disease at the histo-pathological level. Moreover, since a myoblast-to-fibroblast conversion has been reported in aged as well as distrophyc skeletal muscle (Brack et al., 2007; Pessina et al., 2015) , ESR4 will use the Pax7-Cre/Rosa26-YFP reporter mice to trace these cells and analyse their fate in aging and in disease (mdx).
Objectives
To understand the origin, the fate and the role of different fibrogenic precursors during the progression of muscle dystrophy and in aging muscle using lineage-tracing mouse models
Duration
36 months
Enrolment in Doctoral degree
PhD programme in Biomedicine, at the Pompeu Fabra University (http://www.upf.edu/phd-biomedicine/)
References
Brack, A.S., Conboy, M.J., Roy, S., Lee, M., Kuo, C.J., Keller, C., and Rando, T.A. (2007). Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807-810.
Leung, D.G., and Wagner, K.R. (2013). Therapeutic advances in muscular dystrophy. Annals of Neurology 74, 404–411.
Munoz-Canoves, P., and Serrano, A.L. (2015). Macrophages decide between regeneration and fibrosis in muscle. Trends Endocrinol Metab 26, 449-450.
Pessina, P., Kharraz, Y., Jardi, M., Fukada, S., Serrano, A.L., Perdiguero, E., and Munoz-Canoves, P. (2015). Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy. Stem Cell Reports 4, 1046-1060.
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.
Tidball, J.G., and Villalta, S.A. (2010). Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 298, R1173-1187.
