Therapeutic effects of adipose-derived mesenchymal stem cells against brain death-induced remote organ damage and post-heart transplant acute rejection

Hon-Kan Yip; Mel S Lee; Cheuk-Kwan Sun; Kuan-Hung Chen; Han-Tan Chai; Pei-Hsun Sung; Kun-Chen Lin; Sheung-Fat Ko; Chun-Man Yuen; Chu-Feng Liu; Pei-Lin Shao; Fan-Yen Lee

doi:10.18632/oncotarget.21433

Therapeutic effects of adipose-derived mesenchymal stem cells against brain death-induced remote organ damage and post-heart transplant acute rejection

Oncotarget. 2017 Sep 30;8(65):108692-108711. doi: 10.18632/oncotarget.21433. eCollection 2017 Dec 12.

Authors

Hon-Kan Yip^{1

2

3

4

5}, Mel S Lee⁶, Cheuk-Kwan Sun⁷, Kuan-Hung Chen⁸, Han-Tan Chai¹, Pei-Hsun Sung¹, Kun-Chen Lin⁸, Sheung-Fat Ko⁹, Chun-Man Yuen¹⁰, Chu-Feng Liu¹¹, Pei-Lin Shao⁵, Fan-Yen Lee¹²

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
² Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
³ Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁴ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
⁵ Department of Nursing, Asia University, Taichung, Taiwan.
⁶ Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁷ Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan.
⁸ Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁹ Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹⁰ Division of Neurosurgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹¹ Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹² Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Abstract

We tested the hypothesis that allogenic adipose-derived mesenchymal stem cells (ADMSCs) alleviated brain death (BD)-induced remote organ damage and events of post heart-transplant acute rejection. To determine the impact of BD on remote organ damage, adult-male F344 rats (n=24) were categorized sham-control (SC), BD and BD^MSC (allogenic ADMSC/1.2 × 10⁶ cells/derived from F344 by intravenous transfusion 3 h after BD procedure). To determine the protective effect of allogenic ADMSCs, animals (n=8/each group in F344/Lewis) were categorized into groups BD-T(F344 heart transplanted into Lewis by 6h after BD), BD-T^MSC(D1/3) (BD induction for 6h then heart transplantation, and allogenic ADMSCs transfusion at days 1 and 5 after heart transplantation), BD-T^MSC(3h) (BD + ADMSC/1.2 × 10⁶ cells at 3h and heart transplantation at 6h after BD) and BD-T^{MSC(3h, D1/3)} [BD + ADMSC/1.2 × 10⁶ cells at 3h and heart transplantation at 6h after BD, then ADMSC therapy by days 1/3]. At day 5 post procedure, liver, kidney and heart specimens showed higher molecular-cellular levels of inflammation, immune reaction, apoptosis and fibrosis in BD than in SC that were reversed in BD^MSC (all P < 0.0001). These molecular-cellular expressions and circulating/splenic levels of innate/adoptive immune cells were higher in BD-T, lowest in BD-T^{MSC(3h, D1/3)} and higher BD-T^MSC(3h) in than BD-T^MSC(D1/3), whereas heart function showed an opposite pattern among the four groups (all P < 0.001). In conclusion, ADMSCs suppressed BD-caused remote organ damage and heart-transplant rejection.

Keywords: brain death; heart transplantation; immunogenicity; inflammation; remote organ damage.