Open AccessChimerism through the activation of invariant natural killer T cells prolongs graft survival after transplantation of induced pluripotent stem cell–derived allogeneic cardiomyocytes
Author(s) -
Shohei Yoshida,
Shigeru Miyagawa,
Takashi Matsuzaki,
Yasuyuki Ishii,
Emi Fukuda-Kawaguchi,
Takuji Kawamura,
Akira Kawamura,
Yuki Nakamura,
Köichi Toda,
Yoshiki Sawa
Publication year - 2022
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0264317
Subject(s) - chimera (genetics) , induced pluripotent stem cell , transplantation , transplantation chimera , stem cell , immunology , medicine , biology , cancer research , microbiology and biotechnology , embryonic stem cell , haematopoiesis , hematopoietic cell , biochemistry , gene
The loss of functional cells through immunological rejection after transplantation reduces the efficacy of regenerative therapies for cardiac failure that use allogeneic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Recently, mixed-chimera mice with donor-specific immunotolerance have been established using the RGI-2001 (liposomal formulation of α-galactosyl ceramide) ligand, which activates invariant natural killer T (iNKT) cells. The present study aimed to investigate whether mixed chimerism, established using RGI-2001, prolongs graft survival in allogeneic iPSC-CM transplantation. Mixed-chimera mice were established via combinatorial treatment with RGI-2001 and anti-CD154 antibodies in an irradiated murine bone marrow transplant model. Luciferase-expressing allogeneic iPSC-CMs were transplanted into mixed-chimera and untreated mice, followed by in vivo imaging. RGI-2001 enhanced iNKT cell activation in mice, and mixed chimerism was successfully established. In vivo imaging revealed that while the allografts were completely obliterated within 2 weeks when transplanted to untreated mice, their survivals were not affected in the mixed-chimera mice. Furthermore, numerous CD3+ cells infiltrated allografts in untreated mice, but fewer CD3+ cells were present in mixed-chimera mice. We conclude that mixed-chimera mice established using RGI-2001 showed prolonged graft survival after allogeneic iPSC-CM transplantation. This donor-specific immunotolerance might increase the efficacy of regenerative therapies for heart failure with allogeneic iPSC-CMs.