Abstract 15053: Hypoxic Preconditioning Improves the Effectiveness of Bone Marrow Mesenchymal Stem Cells for Cardiac Repair in Cynomolgus Monkeys With Myocardial Infarction

• DOI: 10.1161/circ.132.suppl_3.15053
• Publication Date: 2024-04-23T10:56:22Z
• Authors: Xin Yang Hu; Yinchuan Xu; Yan Wu; Jing Zhao; Zhiwei Zhong; Lihong Chen; Jing Jin; Rongrong Wu; Qingju Li; Yingchao Wang; Haifeng Cheng; Minjian Kong; Fengjiang Zhang; Qi Chen; Chen Wang; Hongwei Zhan; Youqi Fan; Lei Yu; Qian Yang; Jianzhong Sun; Qian Li; Jie Liang; Wei Zhu; Jinghai Chen; Hong Yu; Jianyi Zhang; Jian’an Wang

Background: Experiments in rodents have shown that hypoxic preconditioning (HP) can increase the therapeutic effectiveness of transplanted bone-marrow mesenchymal stem cells (MSCs) for myocardial infarction (MI). Here, we investigated whether the benefits associated with HP-MSC transplantation are also observed in non-human primates with MI.

Methods: Allogeneic MSCs engineered to express GFP via lentiviral transfection were cultured in 21% oxygen (N-MSCs) or in 0.5% oxygen (HP-MSCs) for 24 hours. MI was surgically induced in Cynomolgus monkeys by ligating the left anterior-descending coronary artery distal to the first diagonal branch. 30 minutes later, 28 monkeys were each treated with 10 million MSCs intramyocardially injection. (N-MSCs: 13 monkeys; HP-MSCs: 15 monkeys). 11 additional monkeys treated with saline were served as control. LVEF and infarct sizes (IS) were measured echocardiographically, and the change in each parameter (ΔLVEF, ΔIS) was calculated by subtracting measurements taken 3 days post MI from measurements taken 28 days post MI. Incidents of ventricular arrhythmia were continuously detected via telemetry. Vascularity, arteriole density, proliferation, and endogenous progenitor-cell activation were evaluated via immunofluorescent assessments of CD31, SMA, Ki67, and c-kit expression, respectively; Engraftment was evaluated via RT-PCR measurements of GFP expression. Apoptosis was assessed with TUNEL staining, and the expression of pro-survival and/or pro-angiogenic genes was evaluated via immunoblot.

Results: HP increased the expression of several pro-survival/pro-angiogenic factors (Ang 1, EPO, HGF, PDGF-BB) in cultured MSCs, and treatment with HP-MSCs, but not with N-MSCs was associated with significant improvements in ΔLVEF, ΔIS, vascularity, proliferation, and apoptosis. Vascularity and proliferation were also greater in HP-MSC animals than in N-MSC animals, and HP improved measurements of cell engraftment at Day 3, but not at Day 28. The incidence of arrhythmia (PVCs or NSVT) in all three experimental groups was similar.

Conclusions: HP improved the effectiveness of MSC transplantation for the treatment of MI in non-human primates without increasing the occurrence of arrhythmogenic complications.