Transplantation of Rat Mesenchymal Stem Cells Overexpressing Hypoxia-Inducible Factor 2α Improves Blood Perfusion and Arteriogenesis in a Rat Hindlimb Ischemia Model.

Weifeng Lu,Yi Si,Shichai Hong,Xiaoli Chen,Zhengyu Shi,Weiguo Fu

doi:10.1155/2017/3794817

Abstract

Mesenchymal stem cells (MSCs) have been increasingly tested in cell-based therapy to treat numerous diseases. Genetic modification to improve MSC behavior may enhance posttransplantation outcome. This study aims to test the potential therapeutic benefits of rat bone marrow MSCs overexpressing hypoxia-inducible factor 2α (rMSCsHIF-2α) in a rat hindlimb ischemia model. PBS, rMSCs, or rMSCsHIF-2α were injected into rat ischemic hindlimb. Compared with the injection of PBS or rMSCs, transplantation of rMSCsHIF-2α significantly improved blood perfusion, increased the number of vessel branches in the muscle of the ischemic hindlimb, and improved the foot mobility of the ischemic hindlimb (all P < 0.05). rMSCHIF-2α transplantation also markedly increased the expression of proangiogenic factors VEGF, bFGF, and SDF1 and Notch signaling proteins including DII4, NICD, Hey1, and Hes1, whereas it reduced the expression of proapoptotic factor Bax in the muscle of the ischemic hindlimb. Overexpression of HIF-2α did not affect rMSC stemness and proliferation under normoxia but significantly increased rMSC migration and tube formation in matrigel under hypoxia (all P < 0.05). RMSCsHIF-2α stimulated endothelial cell invasion under hypoxia significantly (P < 0.05). Genetic modification of rMSCs via overexpression of HIF-2α improves posttransplantation outcomes in a rat hindlimb ischemia model possibly by stimulating proangiogenic growth factors and cytokines.

Highlights

Mesenchymal stem cells (MSCs) are multipotent stem cells and capable to differentiate into a variety of cell types, such as osteocytes, adipocytes, and chondrocytes
To investigate the molecular mechanism underlying the beneficial effect of rMSCHIF-2α transplantation, we examined the expression of growth factors and Hypoxia-inducible factors (HIFs)-2α targeting molecules in the muscle tissue of the ischemic limb and serum angiopoietin (Ang) levels
We found that the rMSCHIF-2α transplantation significantly improved the blood perfusion in the ischemic limb compared to rat bone marrow MSCs (rMSCs) or PBS injection, and foot mobility of the ischemic limb was significantly improved by rMSCHIF-2α transplantation

Summary

Introduction

Mesenchymal stem cells (MSCs) are multipotent stem cells and capable to differentiate into a variety of cell types, such as osteocytes, adipocytes, and chondrocytes. The proliferation rate of MSCs is relatively low [3, 4]; oxidative stress during isolation may induce apoptosis [5, 6]. Tissues containing MSCs usually have low oxygen pressure. The oxygen pressure is 1–7% and 1.5–5% in bone marrow and female reproductive tissues, respectively [7, 8]. Ma and colleagues have demonstrated that oxygen pressure in MSC niche is approximately 2–8% [9]. Normoxic in vitro culturing condition can induce oxidative stress in MSCs, leading to apoptosis [10, 11]. Accumulating in vivo and in vitro evidence supports that hypoxic preconditioning can prevent apoptosis and enhance MSC survival [12,13,14,15].

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