Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell
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Curated by eLife
Evaluation Summary:
This manuscript investigates the role of role of the VEGFA signaling cascade, which is widely known to regulate formation of blood vessels, in muscle satellite cells and muscular diseases. on studying the relationship between muscle stem cells (MuSCs) and blood vessels. The authors identified the FLT1-AKT1 axis as an important effector of VEGFA on MuSC survival. They conducted a series of in silico, in vitro and in vivo experiments and showed that VEGFA-FLT1-AKT signaling promotes satellite cell survival both the physiologic and myopathy conditions. The paper will be interesting not only for muscle biologists, but also cell biologists and the general life science field.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #4 agreed to share their name with the authors.)
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Abstract
Endothelial and skeletal muscle lineages arise from common embryonic progenitors. Despite their shared developmental origin, adult endothelial cells (ECs) and muscle stem cells (MuSCs; satellite cells) have been thought to possess distinct gene signatures and signaling pathways. Here, we shift this paradigm by uncovering how adult MuSC behavior is affected by the expression of a subset of EC transcripts. We used several computational analyses including single-cell RNA-seq (scRNA-seq) to show that MuSCs express low levels of canonical EC markers in mice. We demonstrate that MuSC survival is regulated by one such prototypic endothelial signaling pathway (VEGFA-FLT1). Using pharmacological and genetic gain- and loss-of-function studies, we identify the FLT1-AKT1 axis as the key effector underlying VEGFA-mediated regulation of MuSC survival. All together, our data support that the VEGFA-FLT1-AKT1 pathway promotes MuSC survival during muscle regeneration, and highlights how the minor expression of select transcripts is sufficient for affecting cell behavior.
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Evaluation Summary:
This manuscript investigates the role of role of the VEGFA signaling cascade, which is widely known to regulate formation of blood vessels, in muscle satellite cells and muscular diseases. on studying the relationship between muscle stem cells (MuSCs) and blood vessels. The authors identified the FLT1-AKT1 axis as an important effector of VEGFA on MuSC survival. They conducted a series of in silico, in vitro and in vivo experiments and showed that VEGFA-FLT1-AKT signaling promotes satellite cell survival both the physiologic and myopathy conditions. The paper will be interesting not only for muscle biologists, but also cell biologists and the general life science field.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with …
Evaluation Summary:
This manuscript investigates the role of role of the VEGFA signaling cascade, which is widely known to regulate formation of blood vessels, in muscle satellite cells and muscular diseases. on studying the relationship between muscle stem cells (MuSCs) and blood vessels. The authors identified the FLT1-AKT1 axis as an important effector of VEGFA on MuSC survival. They conducted a series of in silico, in vitro and in vivo experiments and showed that VEGFA-FLT1-AKT signaling promotes satellite cell survival both the physiologic and myopathy conditions. The paper will be interesting not only for muscle biologists, but also cell biologists and the general life science field.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #4 agreed to share their name with the authors.)
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Joint Public Review:
The authors have previously reported on the effects on skeletal muscle of Flt1 loss of function in endothelial cells, including amelioration of the dystrophic phenotype. To better understand this mechanism, they now identify a low level of endothelial cell gene signature in satellite cells and report that VEGFA-FLT1 axis functions as a pro-survival signal in SCs in response to acute muscle injury and in a mouse model of Duchenne muscular dystrophy. Bulk and scRNA sequencing analyses with robust controls were employed and results confirmed using RNA scope on sections. Interestingly, FLK1 has been considered as the receptor for VEGFA signaling, and FLT1 is considered to be a decoy receptor, with stronger affinity for VEGFA, but weaker cytoplasmic signaling. The authors determine that VEGFA binding to Flt1 in SCs …
Joint Public Review:
The authors have previously reported on the effects on skeletal muscle of Flt1 loss of function in endothelial cells, including amelioration of the dystrophic phenotype. To better understand this mechanism, they now identify a low level of endothelial cell gene signature in satellite cells and report that VEGFA-FLT1 axis functions as a pro-survival signal in SCs in response to acute muscle injury and in a mouse model of Duchenne muscular dystrophy. Bulk and scRNA sequencing analyses with robust controls were employed and results confirmed using RNA scope on sections. Interestingly, FLK1 has been considered as the receptor for VEGFA signaling, and FLT1 is considered to be a decoy receptor, with stronger affinity for VEGFA, but weaker cytoplasmic signaling. The authors determine that VEGFA binding to Flt1 in SCs promotes AKT-signaling cascade to support cell survival.
However, the results obtained in vivo need to be reinforced. Specifically, is not clear whether the authors measured satellite cells specifically, or survival, or total muscle cell (myocyte, endothelial, inflammatory, smooth muscle....) survival. Also, since the authors used Pax7tdT mice they should be able to track the fate of VegfA+/Hyper, VegfaKO or Flt1KO satelite cells upon injury and to quantify the number and/or percentage of tomato+ myocytes after injury in each model reflecting the specific consequences of impaired VEGFA signaling in satellite cells. While measuring fibrosis may indeed reflect a myocyte loss, measuring myocyte diameter more likely reflects myocyte differentiation which is proposed (in vitro) not to be modulated by VEGFA-FLT1 signaling. Some methods also need quantification and clarification. Overall the results support their conclusions and the work will be useful for research groups interested in understanding the developmental links between skeletal muscle and blood vascular lineages.
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