Valproic acid stimulates myogenesis in pluripotent stem cell-derived mesodermal progenitors in a NOTCH-dependent manner

Natacha Breuls,Christophe Deroose,Maurilio Sampaolesi,Laura Yedigaryan,Nefele Giarratana,Gabriel Miró Garrido,Stephane Heymans,Paolo Carai,Adrian Ranga

doi:10.1038/s41419-021-03936-w

Abstract

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.

Highlights

Muscular dystrophies (MDs) are a debilitating group of muscle disorders for which no cure exists
Chemically defined mesodermal progenitors have the ability to differentiate into the myogenic and cardiac lineages In order to obtain chemically defined MiPs (cdMiPs), human Induced pluripotent stem cells (iPSCs) were differentiated for four days following a serum-free monolayer approach (Fig. 1A)
The results of scRNAseq analysis show that valproic acid (VPA) treatments increase the number of myogenic progenitors, affecting gene transcription. Dual progenitors targeting both skeletal and cardiac muscles are of great interest to target the most debilitating manifestation of MDs

Summary

Introduction

Muscular dystrophies (MDs) are a debilitating group of muscle disorders for which no cure exists. Patients suffer from progressive deterioration of the skeletal muscles, leading to a decreased walking ability, and develop severe cardiomyopathy later on [1]. These patients would benefit from a cellular therapy capable of targeting both striated muscle types. Induced pluripotent stem cells (iPSCs) have a high proliferative capacity and can differentiate towards all three embryonic lineages. These characteristics make iPSCs an attractive cell type for regenerative medicine. As fibroblasts are easier to obtain and a more attractive source to generate iPSCs, strategies need to be developed to overcome this difference

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