TY - JOUR
T1 - Valproic acid stimulates myogenesis in pluripotent stem cell-derived mesodermal progenitors in a NOTCH-dependent manner
AU - Breuls, Natacha
AU - Giarratana, Nefele
AU - Yedigaryan, Laura
AU - Garrido, Gabriel Miro
AU - Carai, Paolo
AU - Heymans, Stephane
AU - Ranga, Adrian
AU - Deroose, Christophe
AU - Sampaolesi, Maurilio
N1 - Funding Information:
NB would like to thank Jordi Camps and Jens van Herck for the help in performing the SMART-Seq2 and the Master students Zeger Derynck and Laura Danti for their help. Furthermore, a big thanks to Prof. Olivier Pourquié who kindly provided the MSNG1-Venus reported cell line. This work was supported by INTERREG - Euregio Meuse-Rhine (GYM—Generate your muscle 2020-EMR116), FWO (G0D4517N), C1-KU Leuven grant 3DMUSYC (C14/17/111), and Rondoufonds voor Duchenne Onderzoek
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/7/5
Y1 - 2021/7/5
N2 - Muscular dystrophies are debilitating neuromuscular disorders for which no cure exists. As this disorder affects both cardiac and skeletal muscle, patients would benefit from a cellular therapy that can simultaneously regenerate both tissues. The current protocol to derive bipotent mesodermal progenitors which can differentiate into cardiac and skeletal muscle relies on the spontaneous formation of embryoid bodies, thereby hampering further clinical translation. Additionally, as skeletal muscle is the largest organ in the human body, a high myogenic potential is necessary for successful regeneration. Here, we have optimized a protocol to generate chemically defined human induced pluripotent stem cell-derived mesodermal progenitors (cdMiPs). We demonstrate that these cells contribute to myotube formation and differentiate into cardiomyocytes, both in vitro and in vivo. Furthermore, the addition of valproic acid, a clinically approved small molecule, increases the potential of the cdMiPs to contribute to myotube formation that can be prevented by NOTCH signaling inhibitors. Moreover, valproic acid pre-treated cdMiPs injected in dystrophic muscles increase physical strength and ameliorate the functional performances of transplanted mice. Taken together, these results constitute a novel approach to generate mesodermal progenitors with enhanced myogenic potential using clinically approved reagents.
AB - Muscular dystrophies are debilitating neuromuscular disorders for which no cure exists. As this disorder affects both cardiac and skeletal muscle, patients would benefit from a cellular therapy that can simultaneously regenerate both tissues. The current protocol to derive bipotent mesodermal progenitors which can differentiate into cardiac and skeletal muscle relies on the spontaneous formation of embryoid bodies, thereby hampering further clinical translation. Additionally, as skeletal muscle is the largest organ in the human body, a high myogenic potential is necessary for successful regeneration. Here, we have optimized a protocol to generate chemically defined human induced pluripotent stem cell-derived mesodermal progenitors (cdMiPs). We demonstrate that these cells contribute to myotube formation and differentiate into cardiomyocytes, both in vitro and in vivo. Furthermore, the addition of valproic acid, a clinically approved small molecule, increases the potential of the cdMiPs to contribute to myotube formation that can be prevented by NOTCH signaling inhibitors. Moreover, valproic acid pre-treated cdMiPs injected in dystrophic muscles increase physical strength and ameliorate the functional performances of transplanted mice. Taken together, these results constitute a novel approach to generate mesodermal progenitors with enhanced myogenic potential using clinically approved reagents.
KW - RNA-SEQ
KW - INDUCTION
KW - EXPANSION
U2 - 10.1038/s41419-021-03936-w
DO - 10.1038/s41419-021-03936-w
M3 - Article
C2 - 34226515
SN - 2041-4889
VL - 12
JO - Cell Death & Disease
JF - Cell Death & Disease
IS - 7
M1 - 677
ER -