Use of a non-oxidizable form of HMGB1 for muscle repair therapies.
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) and in aging (Serrano and Munoz-Canoves, 2017).
We will focus on how the inflammatory, myogenic and vascular components integrate to coordinate muscle regeneration and how fibrosis develops in pathological conditions. We will investigate the role of HMGB1, a nuclear redox-sensitive protein that acts extracellularly as an alarmin to modulate inflammation or tissue repair, depending on its redox state (Tirone et al., 2018; Venereau et al., 2013).
ESR12 will identify the cell types that are the source of HMGB1 during muscle regeneration, by using mice knockout for HMGB1 in muscles (Tg:Hmgb1fl/fl::MyoD-Cre), in endothelial cells (Tg:Hmgb1fl/fl::Cdh5-CreERT2) or in all cells (Tg:Hmgb1fl/fl::R26-CreERT2), to evaluate the contribution of HMGB1 derived from these specific cell types to muscle regeneration, satellite cells (SCs) activation and maintenance of the SC pool, after acute injury (by cardiotoxin injection, CTX). HMGB1 is a potent activator and chemoattractant of SCs through CXCR4 receptor. ESR12 will investigate the signaling pathways (PI3K, Akt, mTOR and MAPK) downstream of CXCR4 mediating HMGB1 activities in SCs. ESR12 will also contribute to evaluate the potential therapeutic effect of HMGB1 in mouse model of muscle pathologies.
To Identify the cell types that are the source of HMGB1 during muscle regeneration and the signaling pathways mediating HMGB1 activities in SCs
To study if HMGB1 can be used to optimize the ex-vivo expansion and the engraftment of stem cells in muscle
To assess the therapeutic effect of HMGB1
Enrolment in Doctoral degree
Ph.D. Programme in Translational and Molecular Medicine (DIMET), University of Milano Bicocca (www.dimet.org)
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.
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.
Tirone, M., Tran, N.L., Ceriotti, C., Gorzanelli, A., Canepari, M., Bottinelli, R., Raucci, A., Di Maggio, S., Santiago, C., Mellado, M., et al. (2018). High mobility group box 1 orchestrates tissue regeneration via CXCR4. J Exp Med 215, 303-318.
Venereau, E., Schiraldi, M., Uguccioni, M., and Bianchi, M.E. (2013). HMGB1 and leukocyte migration during trauma and sterile inflammation. Molecular immunology 55, 76-82.