Study of the molecular mechanism of Endothelial to Mesenchymal Transition during muscle regeneration and crosstalk with the immune system in vivo and in vitro.
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 (Leung and Wagner, 2013).
We will focus on how the inflammatory and vascular components integrate to coordinate muscle regeneration and how the process of Endothelial to Mesenchymal Transition (EndoMT) contributes to fibrosis in pathological conditions (Piera-Velazquez et al., 2016; Tirone et al., 2019; Zordan et al., 2014) (Iavarone et al., 2020).
To investigate the molecular mechanism of EndoMT in vivo, ESR1 will FACS-sort endothelial derived cells and macrophages from endothelial cells (ECs) specific lineage tracing mice in different EndoMT inducing conditions and at different time points.
ESR1 will investigate the pathways activated in pathological EndoMT by RNA and protein expression analyses, including RNAseq, and upon specific inhibition to identify new pathways that could serve as potential therapeutic targets.
ESR1 will also perform genome-wide epigenetic analyses of EC progenitors and macrophages to gain insight into their chromatin state and into the dynamic changes of chromatin during EndoMT, and correlate this with the transcriptional profile.
In addition, ESR1 will contribute to the optimization of an in vitro systems to study the interaction between endothelial progenitors and macrophages.
- To characterize EC progenitors in vivo during muscle injury in an altered inflammatory environment
To characterize signalling pathways and the chromatin landscape in EC progenitors and macrophages during EndoMT in acute muscle regeneration
To develop new in vitro systems to mimic the vascular niche and macrophage-vascular progenitor interactions to dissect signalling pathways
Enrolment in Doctoral degree
Ph.D. Programme in Translational and Molecular Medicine (DIMET), University of Milano Bicocca (www.dimet.org)
Iavarone, F., Guardiola, O., Scagliola, A., Andolfi, G., Esposito, F., Serrano, A., Perdiguero, E., Brunelli, S., Munoz-Canoves, P., and Minchiotti, G. (2020). Cripto shapes macrophage plasticity and restricts EndMT in injured and diseased skeletal muscle. EMBO Rep 21, e49075.
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.
Piera-Velazquez, S., Mendoza, F.A., and Jimenez, S.A. (2016). Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases. J Clin Med 5.
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.
Tirone, M., Giovenzana, A., Vallone, A., Zordan, P., Sormani, M., Nicolosi, P.A., Meneveri, R., Gigliotti, C.R., Spinelli, A.E., Bocciardi, R., et al. (2019). Severe Heterotopic Ossification in the Skeletal Muscle and Endothelial Cells Recruitment to Chondrogenesis Are Enhanced by Monocyte/Macrophage Depletion. Front Immunol 10, 1640.
Zordan, P., Rigamonti, E., Freudenberg, K., Conti, V., Azzoni, E., Rovere-Querini, P., and Brunelli, S. (2014). Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration. Cell death & disease 5, e1031-1014.