title: Smad1/5/8 are myogenic regulators of murine and human mesoangioblasts.
abstract: Mesoangioblasts (MABs) are vessel-associated stem cells that express pericyte marker genes and participate in skeletal muscle regeneration. Molecular circuits that regulate the myogenic commitment of MABs are still poorly characterized. The critical role of bone morphogenetic protein (BMP) signalling during proliferation and differentiation of adult myogenic precursors, such as satellite cells, has recently been established. We evaluated whether BMP signalling impacts on the myogenic potential of embryonic and adult MABs both in vitro and in vivo. Addition of BMP inhibited MAB myogenic differentiation, whereas interference with the interactions between BMPs and receptor complexes induced differentiation. Similarly, siRNA-mediated knockdown of Smad8 in Smad1/5-null MABs or inhibition of SMAD1/5/8 phosphorylation with Dorsomorphin (DM) also improved myogenic differentiation, demonstrating a novel role of SMAD8. Moreover, using a transgenic mouse model of Smad8 deletion, we demonstrated that the absence of SMAD8 protein improved MAB myogenic differentiation. Furthermore, once injected into α-Sarcoglycan (Sgca)-null muscles, DM-treated MABs were more efficacious to restore α-sarcoglycan (αSG) protein levels and re-establish functional muscle properties. Similarly, in acute muscle damage, DM-treated MABs displayed a better myogenic potential compared with BMP-treated and untreated cells. Finally, SMADs also control the myogenic commitment of human MABs (hMABs). BMP signalling antagonists are therefore novel candidates to improve the therapeutic effects of hMABs.
authors.affiliation: Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium Laboratory of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Domiziana
authors.initials: D
authors.lastname: Costamagna
authors.affiliation: Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
authors.forename: Mattia
authors.initials: M
authors.lastname: Quattrocelli
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Florence
authors.initials: F
authors.lastname: van Tienen
authors.affiliation: Laboratory for Developmental Signalling, VIB Center for the Biology of Disease, Department of Human Genetics, KU Leuven, Leuven, Belgium Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Umans
authors.affiliation: Department of Neurology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Irineus F M
authors.initials: IF
authors.lastname: de Coo
authors.affiliation: Laboratory for Developmental Signalling, VIB Center for the Biology of Disease, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
authors.affiliation: Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, Leuven, Belgium Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.affiliation: Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium Division of Human Anatomy, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy maurilio.sampaolesi@med.kuleuven.be.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Sampaolesi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D006801:Humans; D051379:Mice; D024510:Muscle Development / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D020286:Pericytes / Q000166:cytology / Q000378:metabolism; D051898:Smad1 Protein / Q000378:metabolism*; D051902:Smad5 Protein / Q000378:metabolism*; D051904:Smad8 Protein / Q000378:metabolism*
chemical_list: D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein
keywords: BMP signalling; SMAD; mesoangioblast; pericytes; regeneration; skeletal muscle