title: Notch signaling regulates myogenic regenerative capacity of murine and human mesoangioblasts.
abstract: Somatic stem cells hold attractive potential for the treatment of muscular dystrophies (MDs). Mesoangioblasts (MABs) constitute a myogenic subset of muscle pericytes and have been shown to efficiently regenerate dystrophic muscles in mice and dogs. In addition, HLA-matched MABs are currently being tested in a phase 1 clinical study on Duchenne MD patients (EudraCT #2011-000176-33). Many reports indicate that the Notch pathway regulates muscle regeneration and satellite cell commitment. However, little is known about Notch-mediated effects on other resident myogenic cells. To possibly potentiate MAB-driven regeneration in vivo, we asked whether Notch signaling played a pivotal role in regulating MAB myogenic capacity. Through different approaches of loss- and gain-of-function in murine and human MABs, we determined that the interplay between Delta-like ligand 1 (Dll1)-activated Notch1 and Mef2C supports MAB commitment in vitro and ameliorates engraftment and functional outcome after intra-arterial delivery in dystrophic mice. Furthermore, using a transgenic mouse model of conditional Dll1 deletion, we demonstrated that Dll1 ablation, either on the injected cells, or on the receiving muscle fibers, impairs MAB regenerative potential. Our data corroborate the perspective of advanced combinations of cell therapy and signaling tuning to enhance therapeutic efficaciousness of somatic stem cells.
authors.affiliation: Translational Cardiomyology Lab, Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Quattrocelli
authors.affiliation: Translational Cardiomyology Lab, Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Costamagna
authors.affiliation: Translational Cardiomyology Lab, Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Giacomazzi
authors.affiliation: Translational Cardiomyology Lab, Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Camps
authors.affiliation: 1] Translational Cardiomyology Lab, Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven, Belgium [2] Division of Human Anatomy, University of Pavia, Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sampaolesi
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024510:Muscle Development; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1