Abstract
BackgroundThe administration of mesenchymal stem cells (MSCs) remains the most promising approach for cardiac repair after myocardial infarct (MI). However, their poor survival and potential in the ischemic environment limit their therapeutic efficacy for heart repair after MI. The purpose of this study was to investigate the influence of FoxC1-induced vascular niche on the activation of octamer-binding protein 4 (Oct4) and the fate of MSCs under hypoxic/ischemic conditions.MethodsVascular microenvironment/niche was induced by efficient delivery of FoxC1 transfection into hypoxic endothelial cells (ECs) or infarcted hearts. MSCs were cultured or injected into this niche by utilizing an in vitro coculture model and a rat MI model. Survival and neovascularization of MSCs regulated by Oct4 were explored using gene transfer and functional studies.ResultsHere, using gene expression heatmap, we demonstrated that cardiac ECs rapidly upregulated FoxC1 after acute ischemic cardiac injury, contributing to an intrinsic angiogenesis. In vitro, FoxC1 accelerated tube-like structure formation and increased survival of ECs, resulting in inducing a vascular microenvironment. Overexpression of FoxC1 in ECs promoted survival and neovascularization of MSCs under hypoxic coculture. Overexpression of Oct4, a FoxC1 target gene, in MSCs enhanced their mesenchymal-to-endothelial transition (MEndoT) while knockdown of Oct4 by siRNA altering vascularization. In a rat MI model, overexpression of FoxC1 in ischemic hearts increased post-infarct vascular density and improved cardiac function. The transplantation of adOct4-pretreated MSCs into these ischemic niches augments MEndoT, enhanced vascularity, and further improved cardiac function. Consistently, these cardioprotective effects of FoxC1 was abrogated when Oct4 was depleted in the MSCs and was mimicked by overexpression of Oct4.ConclusionsTogether, these studies demonstrate that the FoxC1/Oct4 axis is an essential aspect for survival and neovascularization of MSCs in the ischemic conditions and represents a potential therapeutic target for enhancing cardiac repair.
Highlights
The administration of mesenchymal stem cells (MSCs) remains the most promising approach for cardiac repair after myocardial infarct (MI)
Forkhead box C1 (FoxC1) is highly expressed in ischemic endothelial cells (ECs) We previously demonstrated that the existence of an intrinsic vascular niche appears more beneficial to cardiac repair induced by stem cell therapy after MI, and blood vascular ECs were key cell components in the ischemic niches [52]. von Willebrand factor and CD31 are widely used as blood vascular EC markers [52]
We analyzed transcription factors (TFs) based on gene expression profiles of hypoxic ECs and normal ECs derived from infarcted hearts and normal hearts
Summary
The administration of mesenchymal stem cells (MSCs) remains the most promising approach for cardiac repair after myocardial infarct (MI). Their poor survival and potential in the ischemic environment limit their therapeutic efficacy for heart repair after MI. MSCs secrete angiogenic factors [20] and can repopulate the injured myocardium and restore cardiac function [2, 33]. Ensuring their long-term survival and viability after transplantation remains a challenge [35]. New strategies are needed to maintain MSC survival and resist hypoxic injury
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