Abstract
Embryonic VE-Cadherin-expressing progenitors (eVE-Cad+), including hemogenic endothelium, have been shown to generate hematopoietic stem cells and a variety of other progenitors, including mesoangioblasts, or MABs. MABs are vessel-associated progenitors with multilineage mesodermal differentiation potential that can physiologically contribute to skeletal muscle development and regeneration, and have been used in an ex vivo cell therapy setting for the treatment of muscular dystrophy. There is currently a therapeutic need for molecules that could improve the efficacy of cell therapy protocols; one such good candidate is nitric oxide. Several studies in animal models of muscle dystrophy have demonstrated that nitric oxide donors provide several beneficial effects, including modulation of the activity of endogenous cell populations involved in muscle repair and the delay of muscle degeneration. Here we used a genetic lineage tracing approach to investigate whether the therapeutic effect of nitric oxide in muscle repair could derive from an improvement in the myogenic differentiation of eVE-Cad+ progenitors during embryogenesis. We show that early in vivo treatment with the nitric oxide donor molsidomine enhances eVE-Cad+ contribution to embryonic and fetal myogenesis, and that this effect could originate from a modulation of the properties of yolk sac hemogenic endothelium.
Highlights
Over the last years, the existence of different stem or progenitor cells with myogenic potential has been widely explored
The nitric oxide (NO)-releasing drug molsidomine was administered at the beginning of the pregnancy and the treatment continued until the recovery of the embryos/fetuses as in [12]
We determined the proportions of the macrophage (F4/80+) and non-macrophage subsets in the hematopoietic population, since in our previous work we showed that, amongst the EYFP+ population, mesoangioblast-like cells belonged to the CD31CD45+ F4/80- subpopulation [4]
Summary
The existence of different stem or progenitor cells with myogenic potential has been widely explored. A population of progenitor cells named mesoangioblasts (MABs) has been identified in the embryonic dorsal aorta [2]. They express markers of hemangioblastic, hematopoietic, endothelial and PLOS ONE | DOI:10.1371/journal.pone.0164893. Using a Cre-loxP based genetic lineage tracing system, we have shown that the hemogenic endothelium in the mouse embryo can undergo mesenchymal transition and is the source of CD45+ progenitor cells. These are distinct from embryonic MFs and can give rise both to hematopoietic cells and mesenchymal progenitor cells. The latter bear characteristics of embryonic MABs and are able to physiologically contribute to different mesodermal lineages in the embryo, including the skeletal muscle [4]
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