Skeletal Muscle Regeneration and Muscular Dystrophies
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
Education:
1992 Graduated from High School
1998 Degree cum laude in Biological Sciences – University of Rome “La Sapienza”, Italy
1999-2003 PhD training – Genetics and Molecular Biology – University of Rome “La Sapienza”, Italy
2001 Italian Biological License Examination
2005-2010 Postdoctoral training – Epigenetic regulation of gene expression – European Institute of Oncology (IEO), Milan, Italy
Positions:
2011 December – present: Tenured Researcher, National Council of Research (CNR); Institute of Cellular Biology and Neurobiology – (IBCN) (until September 2019), Institute of Biochemistry and Cell Biology (IBBC) (from October 2019), Rome, Italy
2011 January-November: Senior Post-Doc Fellow, Research fellowship, Department of Medico-Surgical Sciences and Biotechnologies, University of Rome “Sapienza” Italy
2005-2010 Postdoctoral fellowship -Department di Experimental Oncology – European Institute of Oncology-IEO, Milan, Italy
2005 Research fellowship –Institute of Neurobiology and Molecular Medicine (INMM) – National Research Council (CNR), Rome, Italy
2004: Postdoctoral fellowship, CNR- National Council of Research, Institute of Neurobiology and Molecular Medicine (INMM), Rome, Italy
2003 Postdoctoral fellowship – Institute of Neurobiology and Molecular Medicine (INMM) – National Research Council (CNR), Rome, Italy
1999-2003: PhD Fellow, CNR- National Council of Research, Institute of Cell Biology (IBC), Rome, Italy
1996-1998: Undergraduate student – Institute of Cell Biology Institute (IBC), National Research Council (CNR), Rome, Italy.
2007-2010 Four years contract – Department di Experimental Oncology – European Institute of Oncology – IEO, Milan, Italy – financed by MARIE CURIE EXCELLENCE GRANTS
2004 Fondazione Italiana per la Ricerca sul Cancro (FIRC) Postdoctoral fellowship -Institute of Neurobiology and Molecular Medicine (INMM) – National Research Council (CNR), Rome
2003 Postdoctoral fellowship – Institute of Neurobiology and Molecular Medicine (INMM) – National Research Council (CNR), Rome, Italy
1999-2003 PhD student – Cell Biology Institute, National Research Council (CNR), Rome, Italy.
Honours/Awards:
2006- 2010: Four-year post-doctoral Fellow, granted by MARIE CURIE EXCELLENCE GRANTS, European Institute of Oncology (IEO), Milan, Italy
2004 One – year postdoctoral fellowship granted by Fondazione Italiana per la Ricerca sul Cancro (FIRC)
1995 Collaborative Undergraduate fellowship –Library of Institute of Biochemistry University of Rome “Sapienza”, Italy.
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.
Effect of Lactobacillus farciminis supplementation in preventing LPS-induced hippocampal neuroinflammation, in mice. C. Petrella, G. Strimpakos, F. De Santa, M. Fiore, D. Mora, S. Arioli, S. Farioli-Vecchioli. Pharmadvances Vol. 2 (No.1) 2020 April (postit) doi: 10.36118/pharmadvances.01.2020.13
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
Carlomosti F, D’Agostino M, Beji S, Torcinaro A, Rizzi R, Zaccagnini G, Maimone B, Di Stefano V, De Santa F, Cordisco S, Antonini A, Ciarapica R, Dellambra E, Martelli F, Avitabile D, Capogrossi MC, Magenta A. (2017). Oxidative stress-induced miR-200c disrupts the regulatory loop among SIRT1, FOXO1 and eNOS.Antioxid Redox Signal. 2017 Aug 20;27(6):328-344. doi: 10.1089/ars.2016.6643. PMID: 27960536
Francesca De Santa, Ilaria Iosue, Alberto Del Rio, Francesco Fazi. (2013). microRNA biogenesis pathway as therapeutic target for human disease and cancer. Current Pharmaceutical Design, 19(4): 745-764
Francesca De Santa, Iros Barozzi, Flore Mietton, Serena Ghisletti, Sara Polletti, Betsabeh Khoramian Tusi, heiko Muller, Jannis Ragoussis, Chia-Lin Wei, Gioacchino Natoli. A large fraction of extragenic RNA Pol II transcription sites overlap enhancers. Plos Biology, 2010 May 11; 8(5); e1000384
Serena Ghisletti, Iros Barozzi, Flore Mietton, Sara Polletti, Francesca De Santa, Elisa Venturini, Lorna Gregory, Lorne Lonie, Adeline Chew, Chia-Lin Wei, Jiannis Ragoussis, Gioacchino Natoli. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity, 2010 Mar 26, 32(3): 317-28.
Francesca De Santa, Vipin Narang, Zhew Hwee Yap, Betsabeh Khoramian Tusi, Thomas Burgold, Liv Austenaa, Gabriele Bucci, Marieta Caganova, Samuele Notarbartolo, Stefano Casola, Giuseppe Testa, Wing-Kin Sung, Chia-Lin Wei and Gioacchino Natoli (2009). Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. The EMBO Journal (2009) 28, 3341–3352.
Natoli G, Testa G, De Santa F. (2009). The future therapeutic potential of histone demethylases: A critical analysis. Curr Opin Drug Discov Devel. 2009 Sep;12(5):607-15.
Ruggiero T, Trabucchi M, De Santa F, Zupo S, Harfe BD, McManus MT, Rosenfeld MG, Briata P, Gherzi R (2009). LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages. FASEB J. 2009 Sep;23(9):2898-908. Epub 2009 May 7
Thomas Burgold, Fabio Spreafico, Francesca De Santa, Maria Grazia Totaro, Elena Prosperini, Gioacchino Natoli, Giuseppe Testa, (2008). The Histone H3 Lysine 27-Specific Demethylase Jmjd3 Is Required for Neural Commitment. PLoS ONE. 2008 Aug 21;3(8): e3034
Francesca De Santa, Sonia Albini, Eleonora Mezzaroma, Livio Baron, Armando Felsani, and Maurizia Caruso. (2007). pRb-Dependent Cyclin D3 Protein Stabilization Is Required for Myogenic Differentiation. Mol. Cell. Biol. Oct. 2007, Vol 27, No 20, p. 7248-7265
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.
G.Natoli and F. De Santa, (2006). Shaping alternative NF-kB-dependent gene expression programs: new clues to specificity. Cell Death and Differentiation, 2006, 13. 693-696
Magenta, A., Cenciarelli, C., De Santa, F., Fuschi, P., Martelli, F., Caruso, M., and Felsani, A., (2003). MyoD Stimulates Promoter Activity via the CREB/p300 Nuclear Transduction Pathway. Mol. Cell. Biol., 2003, 23. 2893-2906.
Cenciarelli,C., De Santa, F., Puri, P.L., Mattei, E., Ricci, L., Bucci, F., Felsani, A., and Caruso, M. (1999). Critical Role Played by Cyclin D3 in the MyoD-Mediated Arrest of Cell Cycle during Myoblast Differentiation. Mol. Cell. Biol., 1999, 19, 5203-5217
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Post Doctoral Fellows: Graduate Students
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- 2019 – 2020 Source: BeingPharma S.r.l.
Title of the project: Role of BP-002 in gut-brain axis.
Role: Co-Investigator - 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.
Role: Collaborator - 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.
Role: Collaborator - 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