FoxC1-Induced Vascular Niche Improves Survival and Myocardial Repair of Mesenchymal Stem Cells in Infarcted Hearts

Cui

et al. 2021

Preprint

Self Cite

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 limits 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 demonstrate that cardiac ECs rapidly up-regulated 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 increases post infarct vascular density and improves cardiac function. Transplantation of adOct4-pretreated MSCs into these ischemic niches augments MEndoT, enhances vascularity and further improves 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.

Section: Discussionsupporting

confidence: 84%

Oct4-dependent FoxC1 Activation Improves the Survival and Neovascularization of Mesenchymal Stem Cells under Myocardial Ischemia

Zhou

Cui

et al. 2021

Preprint

Self Cite

“…Although MSC transplantation has shown promising results in treating MI, the harsh environment of the ischemic heart, including inflammation and insufficient vascular supply, significantly reduces the cell retention and engraftment of MSCs, leading to a decreased therapeutic efficacy [ 29 , 30 ]. It has been documented that only 0.44% of transplanted MSCs were observed in the heart at 4 days posttransplantation [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Apelin-13 Pretreatment Promotes the Cardioprotective Effect of Mesenchymal Stem Cells against Myocardial Infarction by Improving Their Survival

Stem Cells International

Liang

Han

et al. 2022

Although mesenchymal stem cell- (MSC-) based therapy has shown promising results for myocardial infarction (MI), low cell survival heavily limits its beneficial effects. Apelin plays an essential regulatory role in cell proliferation. This study was aimed at determining whether Apelin-13 pretreatment could improve the survival of MSCs in the ischemic heart and enhance their cardioprotective efficacy against MI. MSCs were pretreated with or without Apelin-13 for 24 hours and then exposed to serum deprivation and hypoxia (SD/H) for 48 hours. The mitochondrial morphology of MSCs was assessed by MitoTracker staining. The apoptosis of MSCs was determined by TUNEL staining. The level of mitochondrial reactive oxygen species (ROS) of MSCs was detected by Mito-Sox staining. MSCs and Apelin-13-pretreated MSCs were transplanted into the peri-infarct region in a mouse MI model. Apelin-13 pretreatment protected MSCs against SD/H-induced mitochondrial fragmentation and apoptosis. Apelin-13 pretreatment reduced ROS generation induced by SD/H in MSCs. Furthermore, Apelin-13 pretreatment enhanced the angiogenesis of MSCs under SD/H conditions. Mechanistically, Apelin-13 pretreatment inhibited SD/H-induced MSC apoptosis by downregulating mitochondrial fission via activation of the ERK pathway, and these effects were partially abrogated by ERK inhibitor U0126. Apelin-13 pretreatment promoted the survival of MSCs in the ischemic heart. Moreover, transplantation with Apelin-13-pretreated MSCs improved heart function and increased angiogenesis accompanied by decreased fibrosis compared with MSC transplantation at 28 days following MI. These findings reveal that pretreatment with Apelin-13 improves MSCs survival and enhances their therapeutic efficacy for MI. Our study provides a novel approach to improve MSC-based therapy for cardiovascular disease.

“…In line with this, overexpression of FoxC1 induced inhibition of cardiac remodeling and resulted in improvement of cardiac function. On the other hand, sustained activation of FoxC1 provided a vascular niche which benefited the survival and function of MSCs transplanted into ischemic hearts [ 54 ]. Our results in ischemic hearts supported the hypothesis of an anti-apoptosis-inducing effect of FoxC1 at a high expression rate, while a lower expression rate decreased engraftment of MSCs.…”

Section: Discussionmentioning

confidence: 99%

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

Zhou

et al. 2021

Stem Cell Res Ther

Self Cite

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.