Group Leader : Francesca De Santa
Topic: Muscle Biology and Pathology
KEYWORDS: Skeletal muscle regeneration; Duchenne Muscular Dystrophy; Inflammation; Macrophages
The general focus of our research activity is the role of inflammation in regeneration of dystrophic skeletal muscles.
Muscular dystrophies are a group of genetic disorders associated with mutations of genes that regulate myofiber integrity. The most common is the Duchenne muscular dystrophy (DMD) and the mdx mouse is the best animal model of DMD. Different cell types are involved in regeneration of dystrophic muscles, especially resident satellite cells (SCs), the muscle stem cells, and fibroadipogenic progenitors (FAPs) and infiltrated immune cells, mainly macrophages (MPs).
The main focus of our research projects is the study of the crosstalk between immune system, mainly macrophages, and resident cell populations in modulating skeletal muscle regeneration and the role of resident and infiltrated cells in mediating therapeutic treatments for DMD. To this end, we recently generated a dystrophic mouse model in which macrophages can be transiently depleted. Specifically, the therapeutic treatments tested include inhibitors of histone deacetylases (HDACi), inhibitors of the activity of micro-RNA (miR), metabolic modulators of macrophages and probiotics. The experimental work includes the use of mouse models and cellular models, immunohistochemistry, histopathological and morphometric analyses, expression analysis also by genome-wide approaches, purification and ex-vivo culture of primary cell populations.
Madaro L*, Torcinaro A*, De Bardi M, Contino FF, Pelizzola M, Diaferia GR, Imeneo G, Bouchè M, Puri PL, De Santa F (2019). Macrophages fine tune satellite cell fate in dystrophic skeletal muscle of mdx mice. Plos Genet. 18;15(10):e1008408. doi: 10.1371/journal.pgen.1008408. PMID:31626629 *co-first authors
Malecova B, Gatto S, Etxaniz U, Passafaro M, Cortez A, Nicoletti C, Giordani L, Torcinaro A, De Bardi M, Bicciato S, De Santa F, Madaro L, Puri PL. (2018) Dynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy. Nat Commun. 10;9(1):3670.
De Santa F, Vitiello L, Torcinaro A, Ferraro E. (2018). The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration. Antioxid Redox Signal. Oct 9. doi: 10.1089/ars.2017.7420. PMID: 30070144.
D’Agostino M#, Torcinaro A#, Madaro L, Marchetti L, Sileno S, Beji S, Salis C, Proietti D, Imeneo G, C Capogrossi M, De Santa F*, Magenta A*. (2018) Role of miR-200c in Myogenic Differentiation Impairment via p66Shc: Implication in Skeletal Muscle Regeneration of Dystrophic mdx Mice. Oxid Med Cell Longev. 13:4814696. doi: 10.1155/2018/4814696. PMID: 29636844.
#co-first authors; *co-last authors
Francesca De Santa, Maria Grazia Totaro, Elena Prosperini, Samuele Notarbartolo, Giuseppe Testa and Gioacchino Natoli. (2007). The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to inhibition of Polycomb-Mediated Gene Silencing. Cell 130, 1083-1094, September 21, 2007.
Programs & Resoucers
2019 – 2020 Source: BeingPharma S.r.l.
Title of the project: Role of BP-002 in gut-brain axis.
2019 – 2020 Source: Duchenne Parent Project Onlus (Italy) – Fast Track
Title of the project: Counteracting inflammation in DMD by promoting pro-regenerative macrophage polarization through a metabolic approach
2016 – 2019 Source: MIUR – The Italian Ministry of Education, Universities and Research; Cluster ALISEI, IRMI (Italian Regenerative Medicine Infrastructure)
Title of the project: Italian Regenerative Medicine Infrastructure (IRMI), a multiregional infrastructure for the development of advanced therapies aimed at organs and tissues regeneration.
2015 – 2017 Source: Duchenne Parent Project –Netherlands.
Title of the project: Role of macrophages in mediating HDACi-based treatment of muscular dystrophy.
Role: Principal Investigator
2013 – 2016 Source: AFM Téléthon France (Association Francaise Contre les Myopathies)
Title of the project: Impact of HDACi on dystrophic muscle: transcriptome and epigenome of macrophages and satellite cells.
Role: Principal Investigator