A Large-Scale Investigation of Hypoxia-Preconditioned Allogeneic Mesenchymal Stem Cells for Myocardial Repair in Nonhuman Primates: Paracrine Activity Without Remuscularization

Xinyang Hu; Yinchuan Xu; Zhiwei Zhong; Yan Wu; Jing Zhao; Yingchao Wang; Haifeng Cheng; Minjian Kong; Fengjiang Zhang; Qi Chen; Jianzhong Sun; Qian Li; Jing Jin; Qingju Li; Lihong Chen; Chen Wang; Hongwei Zhan; Youqi Fan; Qian Yang; Lei Yu; Rongrong Wu; Jie Liang; Jinyun Zhu; Ya Wang; Yiping Jin; Yifan Lin; Fan Yang; Liangliang Jia; Wei Zhu; Jinghai Chen; Hong Yu; Jianyi Zhang; Jian'an Wang

doi:10.1161/CIRCRESAHA.115.307516

A Large-Scale Investigation of Hypoxia-Preconditioned Allogeneic Mesenchymal Stem Cells for Myocardial Repair in Nonhuman Primates: Paracrine Activity Without Remuscularization

Circ Res. 2016 Mar 18;118(6):970-83. doi: 10.1161/CIRCRESAHA.115.307516. Epub 2016 Jan 19.

Authors

Xinyang Hu¹, Yinchuan Xu¹, Zhiwei Zhong¹, Yan Wu¹, Jing Zhao¹, Yingchao Wang¹, Haifeng Cheng¹, Minjian Kong¹, Fengjiang Zhang¹, Qi Chen¹, Jianzhong Sun¹, Qian Li¹, Jing Jin¹, Qingju Li¹, Lihong Chen¹, Chen Wang¹, Hongwei Zhan¹, Youqi Fan¹, Qian Yang¹, Lei Yu¹, Rongrong Wu¹, Jie Liang¹, Jinyun Zhu¹, Ya Wang¹, Yiping Jin¹, Yifan Lin¹, Fan Yang¹, Liangliang Jia¹, Wei Zhu¹, Jinghai Chen¹, Hong Yu¹, Jianyi Zhang², Jian'an Wang²

Affiliations

¹ From the Department of Cardiology (X.H., Y.X., Z.Z., Y. Wu, J. Zhao, Yingchao Wang, J.J., Qingju Li, L.C., C.W., Y.F., R.W., J. L., J.Zhu, Ya Wang, Y.J., Y.L., F.Y., L.J., W.Z., J.C., H.Y., J.W.), Department of Cardiovascular Surgery (H.C., M.K.), Department of Anesthesiology (F.Z., Q.C.), Department of Radiology, (J.S., Qian Li), Department of Nuclear Medicine (H.Z.), and Department of Ultrasonography (Q.Y., L.Y.), Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China; Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China (X.H., Y.X., Z.Z., Y. Wu, J. Zhao, Yingchao Wang, J.J., Qingju Li, L.C., C.W., Y.F., R.W., J.L., J. Zhu, Ya Wang, Y.J., Y.L., F.Y., L.J., W.Z., J.C., H.Y., J.W.); Institute of Translational Medicine, Zhejiang University, Hangzhou, People's Republic of China (J.C.); and Department of Biomedical Engineering, University of Alabama at Birmingham (J. Zhang).
² From the Department of Cardiology (X.H., Y.X., Z.Z., Y. Wu, J. Zhao, Yingchao Wang, J.J., Qingju Li, L.C., C.W., Y.F., R.W., J. L., J.Zhu, Ya Wang, Y.J., Y.L., F.Y., L.J., W.Z., J.C., H.Y., J.W.), Department of Cardiovascular Surgery (H.C., M.K.), Department of Anesthesiology (F.Z., Q.C.), Department of Radiology, (J.S., Qian Li), Department of Nuclear Medicine (H.Z.), and Department of Ultrasonography (Q.Y., L.Y.), Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China; Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China (X.H., Y.X., Z.Z., Y. Wu, J. Zhao, Yingchao Wang, J.J., Qingju Li, L.C., C.W., Y.F., R.W., J.L., J. Zhu, Ya Wang, Y.J., Y.L., F.Y., L.J., W.Z., J.C., H.Y., J.W.); Institute of Translational Medicine, Zhejiang University, Hangzhou, People's Republic of China (J.C.); and Department of Biomedical Engineering, University of Alabama at Birmingham (J. Zhang). jian_an_wang@yahoo.com Jayzhang@uab.edu.

Abstract

Rationale: The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell-based myocardial therapy are needed.

Objective: The present study was designed to test our central hypothesis that hypoxia-preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), nonhuman primate (Cynomolgous monkeys) investigation.

Methods and results: MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then tested in the infarcted hearts of Cynomolgus monkeys (1×10(7) cells per heart). Hypoxia preconditioning increased the expression of several prosurvival/proangiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at day 90 after myocardial infarction were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in normal cultured bone marrow mesenchymal stem cells-treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications.

Conclusions: Hypoxia preconditioning improved the effectiveness of MSCs transplantation for the treatment of myocardial infarction in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted.

Keywords: Cynomolgous monkeys; hypoxia preconditioning; mesenchymal stem cells; myocardial infarction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Hypoxia / physiology
Cell Proliferation / physiology
Cells, Cultured
Ischemic Preconditioning, Myocardial / methods*
Macaca fascicularis
Male
Mesenchymal Stem Cell Transplantation / methods*
Mesenchymal Stem Cells / physiology*
Myocardial Infarction / metabolism
Myocardial Infarction / physiopathology
Myocardial Infarction / therapy*
Myocardial Revascularization*
Paracrine Communication / physiology*
Primates
Transplantation, Homologous / methods