Abstract
Somatic stem cells hold attractive potential for the treatment of muscular dystrophies (MDs). Mesoangioblasts (MABs) constitute a myogenic subset of muscle pericytes and have been shown to efficiently regenerate dystrophic muscles in mice and dogs. In addition, HLA-matched MABs are currently being tested in a phase 1 clinical study on Duchenne MD patients (EudraCT #2011-000176-33). Many reports indicate that the Notch pathway regulates muscle regeneration and satellite cell commitment. However, little is known about Notch-mediated effects on other resident myogenic cells. To possibly potentiate MAB-driven regeneration in vivo, we asked whether Notch signaling played a pivotal role in regulating MAB myogenic capacity. Through different approaches of loss- and gain-of-function in murine and human MABs, we determined that the interplay between Delta-like ligand 1 (Dll1)-activated Notch1 and Mef2C supports MAB commitment in vitro and ameliorates engraftment and functional outcome after intra-arterial delivery in dystrophic mice. Furthermore, using a transgenic mouse model of conditional Dll1 deletion, we demonstrated that Dll1 ablation, either on the injected cells, or on the receiving muscle fibers, impairs MAB regenerative potential. Our data corroborate the perspective of advanced combinations of cell therapy and signaling tuning to enhance therapeutic efficaciousness of somatic stem cells.
Highlights
Notch signaling has been involved in different stages of muscle formation[2] and regeneration.[3,4] The canonical signaling encompasses five ligands (Dll1/3/4, Jagged1/2) and four receptors (Notch1–4); the axis Dll1-Notch[1] appears consistently involved during myogenic fate specification, for example, neural crest-driven somite maturation.[5]
It has been shown that Notch synergizes with Pdgf-bb to convert fetal myoblasts into myogenic pericytes.[11]
We used murine[12] and human MABs,[13] both isolated from somatic muscles as alkaline phosphatase+ (AP+) cells and processed as previously reported[14] (Supplementary Figure 1)
Summary
Notch signaling has been involved in different stages of muscle formation[2] and regeneration.[3,4] The canonical signaling encompasses five ligands (Dll1/3/4, Jagged1/2) and four receptors (Notch1–4); the axis Dll1-Notch[1] appears consistently involved during myogenic fate specification, for example, neural crest-driven somite maturation.[5]. Notch[1] intracellular domain (NICD) robustly committed murine and rat mesenchymal stem cells toward the myogenic fate both in vitro and in vivo.[8] Notch-mediated effects on the regenerative potential of non-satellite resident myogenic cells are still unknown. Mesoangioblasts (MABs) are non-satellite resident myogenic stem cells, able to circulate and regenerate dystrophic skeletal muscles.[9,10] HLA-matched MABs are currently under phase 1 clinical study on Duchenne muscular dystrophy patients (EudraCT #2011-000176-33). In this view, understanding the cell-specific effects and mechanisms of myogenic cues will help improving clinical translation of MABbased therapies in vivo. We asked whether the Dll1-Notch[1] axis regulates the myogenic potential of murine and human MABs and how to tune this pathway to ameliorate in vivo MAB-driven regeneration
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