Oct4-dependent FoxC1 activation improves the survival and neovascularization of mesenchymal stem cells under myocardial ischemia

Abstract

Background The 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. Methods Vascular 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. Results Here, 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. Conclusions Together, 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.

β-Catenin promotes long-term survival and angiogenesis of peripheral blood mesenchymal stem cells via the Oct4 signaling pathway

“…In contrast, Oct4 deficiency completely eliminated PBMSC angiogenesis induced by β-catenin overexpression, as evidenced by decreased vascularization, reduced vascular density, and decreased β-catenin-mediated proangiogenic cytokines. Our previous study demonstrated that Oct4-dependent FoxC1 activation improves the survival and neovascularization of MSCs under myocardial ischemia 50 . All these data might reveal a novel mechanism: β-catenin ameliorated ischemia-related impairment of PBMSC-mediated angiogenesis by inducing MEndoT via an Oct4-dependent mechanism.…”

Oct4 cooperates with c-Myc to improve mesenchymal-to-endothelial transition and myocardial repair of cardiac-resident mesenchymal stem cells

“…Oct4 plays a significant role in the survival and function of various MSCs. Our previous study showed Oct4 as an essential aspect for survival and neovascularization of MSCs in the ischemic conditions [11]. Oct4 can act as a mediator to cooperate with HIF-2α to promote proliferation and function of coronary arterial MSCs in ischemic hearts [10].…”

“…The model of myocardial Isch was established by induction of MI. MI was induced by ligating the left anterior descending coronary artery (LAD) as our previously described [10,11]. MI was confirmed by visual blanching distal to the occlusion site and by echocardiography 24 h after MI.…”

“…From these signaling systems, of note are the following genes: Ang-1, bFGF, HGF, IGF-1 (Insulin-like growth factor-1), Tie2, and VEGF. These genes are all implicated in angiogenesis and MEndoT [11]. Other notable genes are vWF, VEGFR2, and Chd1 (chromatin remodeling factor 1).…”