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Seminar announcement Prof. Sampaolesi- February 19, 2019

Single cell OMICS, cell reprogramming and gene editing to challenge muscular dystrophies

Prof. Maurilio Sampaolesi

Stem Cell and Developmental Biology, KU Leuven, Belgium

Human Anatomy Institute, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Italy

Tuesday, February 19th, 2019 
h. 15.00
Room U 1.1 [MO 51] 
Via Campi 103 - Modena



Muscular dystrophies (MDs) are inherited diseases caused by progressive degeneration of multinucleated skeletal muscle fibers that constitute the most abundant tissue of the human body. Any cell or gene replacement strategy must restore proper gene expression in hundreds of millions of post-mitotic nuclei embedded in a dense sarcoplasm surrounded by thick sarcolemma. Facing this complex situation, clinical trials for MDs have met with modest success, mainly due to the inefficient delivery of viral vectors or donor cells to dystrophic muscles. The current therapeutic approaches for MDs remain mainly steroids and assisted ventilation that cannot counteract fibrosis and fat replacement in dystrophic muscles. Thus, there is an urgent need to develop the next-generation of viral vectors (1, 2) and stem cell-based protocols (3, 4) for the treatment of MDs. 
We provide evidence that epigenetic mechanisms influence the commitment of isogenic induced pluripotent stem (iPS) and mesodermal iPS cell-derived progenitors (MiPs) toward the striated muscle lineages (3). Subsequently, we conjugated the MiP–based approach with genome editing correction and TALEN-corrected canine dystrophic MiPs resulted in functional striated muscle regeneration. In addition, integrating RNA-seq and miRNA-seq data, we defined miRNA cocktails that promote the myogenic potential of human MiPs (4). However, the observed improvement seen with cell-based therapies still does not have an impact on the diffused fibrosis and fat replacement responsible for the loss of mobility in dystrophic patients. Thus, to further gain insight on the cell heterogeneity in skeletal muscle, we recently used single-cell RNA-sequencing to decomplexify interstitial cell populations in healthy and dystrophic skeletal muscles. We identified a CD142 (F3) positive population in mice and humans that is responsible for the inhibition of adipogenesis. The discovery of these adipo-regulatory cells in skeletal muscles aids our understanding regarding the aberrant fat deposition in MDs, paving the way for therapeutic treatments that potentially sustain ambulation in MD patients.
1. Sarcar et al. Nat Commun. 2019 Jan 30;10(1):492.
2. Neyrinck et al. Theranostics. 2018 Apr 14;8(10):2799-2813
3. Quattrocelli et al. J Clin Invest. 2015 Dec;125(12):4463-82
4. Giacomazzi et al. Nat Commun. 2017 Nov 1;8(1) 
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