Smad1/5/8 are myogenic regulators of murine and human mesoangioblasts

Domiziana Costamagna; Mattia Quattrocelli; Florence Van Tienen; Lieve Umans; Irineus F.M. De Coo; An Zwijsen; Danny Huylebroeck; Maurilio Sampaolesi

doi:10.1093/jmcb/mjv059

Smad1/5/8 are myogenic regulators of murine and human mesoangioblasts

Domiziana Costamagna, Mattia Quattrocelli, Florence Van Tienen, Lieve Umans, Irineus F.M. De Coo, An Zwijsen, Danny Huylebroeck, Maurilio Sampaolesi^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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 a-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.

Original language	English (US)
Pages (from-to)	73-87
Number of pages	15
Journal	Journal of molecular cell biology
Volume	8
Issue number	1
DOIs	https://doi.org/10.1093/jmcb/mjv059
State	Published - Feb 2016

Funding

Funding The M.S. laboratory is 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.

Keywords

BMP signalling
Mesoangioblast
Pericytes
Regeneration
SMAD
Skeletal muscle

ASJC Scopus subject areas

General Medicine

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10.1093/jmcb/mjv059

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@article{e3311c22f50446aa96140a4e4cf58748,

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 a-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.",

keywords = "BMP signalling, Mesoangioblast, Pericytes, Regeneration, SMAD, Skeletal muscle",

author = "Domiziana Costamagna and Mattia Quattrocelli and {Van Tienen}, Florence and Lieve Umans and {De Coo}, {Irineus F.M.} and An Zwijsen and Danny Huylebroeck and Maurilio Sampaolesi",

note = "Publisher Copyright: {\textcopyright}The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.",

year = "2016",

month = feb,

doi = "10.1093/jmcb/mjv059",

language = "English (US)",

volume = "8",

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T1 - Smad1/5/8 are myogenic regulators of murine and human mesoangioblasts

AU - Costamagna, Domiziana

AU - Quattrocelli, Mattia

AU - Van Tienen, Florence

AU - Umans, Lieve

AU - De Coo, Irineus F.M.

AU - Zwijsen, An

AU - Huylebroeck, Danny

AU - Sampaolesi, Maurilio

N1 - Publisher Copyright: ©The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.

PY - 2016/2

Y1 - 2016/2

N2 - 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 a-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.

AB - 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 a-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.

KW - BMP signalling

KW - Mesoangioblast

KW - Pericytes

KW - Regeneration

KW - SMAD

KW - Skeletal muscle

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ER -

Smad1/5/8 are myogenic regulators of murine and human mesoangioblasts

Abstract

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