The investigation of innate immune rejection after transplantation of cardiomyocytes derived from induced pluripotent stem cell

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16591
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular surgery
• Research Institution: Osaka University
• Principal Investigator: NAKAMURA YUKI 大阪大学, 医学部附属病院, 医員 (70793313)
• Research Collaborator: TOYOFUKU TOSHIHIKO
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 再生医療 / iPS細胞 / 自然免疫 / NK細胞

Outline of Final Research Achievements

Transplantation of cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) is a promising approach for increasing functional CMs during end-stage heart failure. Although MHC class I matching between donor cells and recipient could reduce acquired immune rejection, innate immune responses may have negative effects on transplanted iPSC-CMs. Here, we demonstrated that natural killer cells (NKCs) infiltrated in iPSC-CM transplants even in a syngeneic mouse model. The depletion of NKCs using an anti-NKC antibody rescued transplanted iPSC-CMs, suggesting that iPSC-CMs activated NKC-mediated innate immunity. iPSC-CMs lost inhibitory MHCs but not activating ligands for NKCs. Re-expression of MHC class I induced by IFN-g as well as suppression of activating ligands by an antibody rescued the transplanted iPSC-CMs. Thus, NKCs impede the engraftment of transplanted iPSC-CMs because of lost MHC class I, and our results provide a basis for an approach to improve iPSC-CM engraftment.

Free Research Field

心臓血管外科

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた知見によりはiPS細胞由来心筋シート移植後のNK細胞による免疫応答を制御することで移植細胞のさらなる長期生着を得られる可能性があり、iPS細胞由来心筋シート移植による不全心へのより効果的な心筋細胞補充を行い、さらなる心機能改善効果を得ることが期待でき、重症心不全治療における再生医療の有効性及び重要性を高めるものであると考えらる。また本研究成果は将来的にiPS細胞由来心筋シート移植を自家移植で行う場合にも有効な治療法となりうることに加えて、iPS細胞を用いた再生医療治療全般に応用可能であると思われ、再生医療分野において汎用性の高いものとなることが期待できる。