Abstract
Transplantation of induced pluripotent stem cell-derived cardiac tissue constructs is a promising regenerative treatment for cardiac failure: however, its tumourigenic potential is concerning. We hypothesised that the tumourigenic potential may be eliminated by the host immune response after allogeneic cell transplantation. Scaffold-free iPSC-derived cardaic tissue sheets of C57BL/6 mouse origin were transplanted into the cardiac surface of syngeneic C57BL/6 mice and allogeneic BALB/c mice with or without tacrolimus injection. Syngeneic mice and tacrolimus-injected immunosuppressed allogeneic mice formed teratocarcinomas with identical phenotypes, characteristic, and time courses, as assessed by imaging tools including 18F-fluorodeoxyglucose-positron emission tomography. In contrast, temporarily immunosuppressed allogeneic mice, following cessation of tacrolimus injection displayed diminished progression of the teratocarcinoma, accompanied by an accumulation of CD4/CD8-positive T cells, and finally achieved complete elimination of the teratocarcinoma. Our results indicated that malignant teratocarcinomas arising from induced pluripotent stem cell-derived cardiac tissue constructs provoked T cell-related host immune rejection to arrest tumour growth in murine allogeneic transplantation models.
Highlights
Nkx2.5, Isl-1, and α-myosin heavy chain (MHC) expression compared with that of undifferentiated DsRed-Luciferase-murine iPSC (miPSC) (* p < 0.05) by real-time PCR. (F) Luminescence intensity and total cell number were positively correlated in vitro. (G) The DsRed-Luciferase-miPSC-derived cardiac tissue construct-sheets were transplanted into the cardiac surface and the abdominal subcutaneous tissue of syngeneic C57BL/6 mice (n = 4)
A pLVSIN-EF1α-DsRed-IRES-LuciferaseNeo lentiviral vector was transfected into 959A2-1 cells, which were treated with neomycin to establish a miPSC line that stably expressed DsRed and Luciferase (DsRed-Luciferase-miPSC; Fig. 1a)
After 14 days of differentiation process, immunohistolabelling of the beating cell clusters demonstrated that all cells expressed DsRed and Luciferase in the cytoplasm, and that troponin I and α-actinin were labelled in the cytoplasm, indicating well-aligned sarcomere structure (Fig. 1c)
Summary
The quantitative BLI study indicated that luminescence intensity was similar regardless of whether cell-sheets were transplanted into the heart or into the subcutaneous tissue. We hypothesised that tumourigenic potential of iPSC-derived cardiac tissue constructs may be affected by the host immune response following allogeneic cell transplantation in the heart. To test this hypothesis, we generated an immunosuppressed allogeneic transplantation model, which is immunologically equivalent to the syngeneic model. The immunological reaction associated with tumour formation was explored by modulating immunosuppressant therapy during the early phase using diagnostic imaging in the allogeneic transplantation model
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