tacrolimus and Teratocarcinoma

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 (18)F-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.

Topics: Animals; Biopsy; Cell Line; Cell Transformation, Neoplastic; Fluorodeoxyglucose F18; Gene Order; Genetic Vectors; Graft Rejection; Immunocompromised Host; Immunosuppressive Agents; Induced Pluripotent Stem Cells; Male; Mice; Mice, Transgenic; Models, Animal; Myocytes, Cardiac; Positron-Emission Tomography; Stem Cell Transplantation; T-Lymphocyte Subsets; Tacrolimus; Teratocarcinoma; Transplantation, Homologous

Amyloid beta-peptide (Abeta) is widely held to be associated with Alzheimer's disease. It was previously demonstrated by our group that Abeta induces cell death by an apoptotic process. We report here that activation of the caspase-3 apoptotic cascade is regulated by calcineurin-mediated BAD dephosphorylation. Calcineurin inhibitors were also proven to be effective by preventing the loss of mitochondrial membrane potential (Delta Psim) induced by Abeta, not allowing cytochrome c release from mitochondria and subsequently caspase-3 activation. Considering the results presented, we argue that calcineurin activation and BAD dephosphorylation are upstream in premitochondrial signaling events leading to caspase-3 activation in Abeta-peptide-treated cells.

Topics: Amyloid beta-Peptides; Apoptosis; bcl-Associated Death Protein; Calcineurin; Calcineurin Inhibitors; Carrier Proteins; Caspase 3; Caspases; Cell Line, Tumor; Cell Survival; Cyclosporine; Drug Interactions; Electron Transport; Humans; Immunosuppressive Agents; Peptide Fragments; Phosphorylation; Tacrolimus; Teratocarcinoma