Over the last years,the existence of different stem cells with myogenic potential has been widely investigated.Be-sides the classical skeletal muscle progenitors represented by satellite cells,numerous multipotent and...Over the last years,the existence of different stem cells with myogenic potential has been widely investigated.Be-sides the classical skeletal muscle progenitors represented by satellite cells,numerous multipotent and embryologi-cally unrelated progenitors with a potential role in muscle differentiation and repair have been identified.In order to conceive a therapeutic approach for degenerative muscle disorders,it is of primary importance to identify an ideal stem cell endowed with all the features for a possible use in vivo.Among all emerging populations,vessel-associated stem cells are a novel and promising class of multipotent progenitors of mesodermal origin and with high myogenic potential which seem to best fit all the requirements for a possible cell therapy.In vitro and in vivo studies have already tested the effectiveness and safety of vessel-associated stem cells in animal models.This leads to the concrete possibility in the future to start pilot human clinical trials,hopefully opening the way to a turn-ing point in the treatment of genetic and acquired muscle disorders.展开更多
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 poorl...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.Weevaluated 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 a-Sarcoglycan(Sgca)-null muscles,DM-treated MABs were more efficacious to restore a-sarcoglycan(aSG)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.展开更多
文摘Over the last years,the existence of different stem cells with myogenic potential has been widely investigated.Be-sides the classical skeletal muscle progenitors represented by satellite cells,numerous multipotent and embryologi-cally unrelated progenitors with a potential role in muscle differentiation and repair have been identified.In order to conceive a therapeutic approach for degenerative muscle disorders,it is of primary importance to identify an ideal stem cell endowed with all the features for a possible use in vivo.Among all emerging populations,vessel-associated stem cells are a novel and promising class of multipotent progenitors of mesodermal origin and with high myogenic potential which seem to best fit all the requirements for a possible cell therapy.In vitro and in vivo studies have already tested the effectiveness and safety of vessel-associated stem cells in animal models.This leads to the concrete possibility in the future to start pilot human clinical trials,hopefully opening the way to a turn-ing point in the treatment of genetic and acquired muscle disorders.
基金supported by EU-FP7 CARE-MI,FWO(#G060612N,#G0A8813N,#G088715N),Opening the Future Campaign EJJ-OPTFUT-02010,and Rondoufonds voor Duchenne Onderzoek.D.C.has been supported by University of Turin.M.Q.is supported by FWO(Postdoctoral Fellowship#1263314N and Travel Grant#V448715N)and AFM(Trampoline Grant#18373).The D.H.lab is supported by a start-up grant of Erasmus MC.We also acknowledge infrastructural funding by the InfraMouse Grant from the Hercules Foundation(ZW09-03,to D.H.and A.Z.)and FWO-V G.0542.13(to A.Z.and D.H.).M.S.,D.H.,and A.Z.are supported by KU Leuven Research Council funding(OT-09/053 and GOA-11/012),the Belgian Agency for Science Policy(Belspo)network IUAPVII-07 DevRepair.
文摘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.Weevaluated 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 a-Sarcoglycan(Sgca)-null muscles,DM-treated MABs were more efficacious to restore a-sarcoglycan(aSG)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.
