Safety and efficacy of intracoronary artery administration of human bone marrow-derived mesenchymal stem cells in STEMI of Lee-Sung pigs-A preclinical study for supporting the feasibility of the OmniMSC-AMI phase I clinical trial

Wannhsin Chen; Chun-Hsiang Hou; Yi-Ling Chen; Hsin-Hsin Shen; Chen-Hsuan Lin; Cheng-Yi Wu; Meng-Hsueh Lin; Chih-Ching Liao; Jun-Jae Huang; Chi-Yu Yang; Yi-Chen Li; Hon-Kan Yip

doi:10.3389/fcvm.2023.1153428

Safety and efficacy of intracoronary artery administration of human bone marrow-derived mesenchymal stem cells in STEMI of Lee-Sung pigs-A preclinical study for supporting the feasibility of the OmniMSC-AMI phase I clinical trial

Front Cardiovasc Med. 2023 Mar 29:10:1153428. doi: 10.3389/fcvm.2023.1153428. eCollection 2023.

Authors

Wannhsin Chen¹, Chun-Hsiang Hou², Yi-Ling Chen^{3

4}, Hsin-Hsin Shen¹, Chen-Hsuan Lin¹, Cheng-Yi Wu¹, Meng-Hsueh Lin¹, Chih-Ching Liao¹, Jun-Jae Huang¹, Chi-Yu Yang², Yi-Chen Li^{5

6

7}, Hon-Kan Yip^{3

4

8

9

10

11

12}

Affiliations

¹ Regeneration Medicine Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.
² Animal Technology Laboratories, Agricultural Technology Research Institute, Miaoli, Taiwan.
³ Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁴ Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
⁵ Center of Cell Therapy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁶ Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁷ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁸ Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
⁹ School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹⁰ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
¹¹ Department of Nursing, Asia University, Taichung, Taiwan.
¹² Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen, China.

Abstract

Background: This study tested whether early left intracoronary arterial (LAD) administration of human bone marrow-derived mesenchymal stem cells (hBMMSCs, called OmniMSCs) in acute ST-segment elevation myocardial infarction (STEMI) of Lee-Sung pigs induced by 90 min balloon-occluded LAD was safe and effective.

Methods and results: Young male Lee-Sung pigs were categorized into SC (sham-operated control, n = 3), AMI-B (STEMI + buffer/21 cc/administered at 90 min after STEMI, n = 6), and AMI-M [acute myocardial infarction (AMI) + hBMMSCs/1.5 × 10⁷/administered at 90 min after STEMI, n = 6] groups. By 2 and 5 months after STEMI, the cardiac magnetic resonance imaging demonstrated that the muscle scar score (MSS) and abnormal cardiac muscle exercise score in the infarct region were significantly increased in the AMI-B than in the SC group that were significantly reversed in the AMI-M group, whereas the left ventricular ejection function by each month (from 1 to 5) displayed an opposite pattern of MSS among the groups (all p < 0.001). By 5 months, histopathological findings of infarct and fibrosis areas and isolectin-B4 exhibited an identical pattern, whereas the cellular expressions of troponin-I/troponin-T/von Willebrand factor exhibited an opposite pattern of MSS among the groups (all p < 0.001). The ST-segment resolution (>80%) was significantly earlier (estimated after 6-h AMI) in the AMI-M group than in the AMI-B group (p < 0.001). The protein expressions of inflammation (IL-1β/TNF-α/NF-κB)/oxidative stress (NOX-1/NOX-2/oxidized protein)/apoptosis (cleaved caspase-3/cleaved PARP)/DNA damage (γ-H2AX) displayed an identical pattern to MSS among the groups, whereas the protein expressions of angiogenesis factors (SDF-1α/VEGF) were significantly and progressively increased from SC, AMI-B, to AMI-M groups (all p < 0.001).

Conclusion: Early intra-LAD transfusion of OmniMSC treatment effectively reduced the infarct size and preserved LV function in porcine STEMI.

Keywords: acute myocardial infarction; balloon occlusion; exogenic mesenchymal stem cells; fibrosis; left ventricular ejection fraction; porcine.

Grants and funding

This research was supported by grants from the Ministry of Economic Affairs, Taiwan (R.O.C.) (109-EC-17-A-22-1467).