Cell-Autonomous Processes That Impair Xenograft Survival into the Cerebellum

Abstract

In immunocompetent animals, numerous factors including the immune system of the host regulate the survival of neuro-glial precursors transplanted into the cerebellum. We transplanted human neuro-glial precursors derived in vitro from partial differentiation of IPS cells into the developing cerebellum of mice and rats before maturation of the host immune system. These approaches should facilitate the development of immune-tolerance for the transplanted cells. However, we found that human cells survived the engraftment and integrated into the host cerebellum and brain stem up to about 1 month postnatally when they were rejected in both species. On the contrary, when we transplanted the same cells in NOD-SCID mice, they survived indefinitely. Our findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts the induction of immune-tolerance to human antigens expressed before completion of the maturation of the immune system. As predicted by our hypothesis, when we engrafted the human neuro-glial precursor cells either in a more mature state or mixed with extracts from adult cerebellum, we prolonged the survival of the graft.

Keywords: Cerebellum; Immune-tolerance; Induced pluripotent stem cells; Xenotransplantation.

Fig. 1

Mouse cerebellum sagittal sections. A Immune-deficient mouse (NOD-SCID: NOD.CB17-Prkdcscid/NCrHsd; Envigo) cerebellum 3 months after the transplant of hiPSdNP. Many processes and cells of human origin expressing green fluorescent protein are visible in the host cerebellar tissue and on the surface of the cerebellum (white asterisk), calbindine immunoreactivity is shown in red. B Immune-competent mouse (CD1) cerebellum 12 months after the transplant in utero of hiPSdNP, no cells of human origin expressing green fluorescent protein are visible, calbindine immunoreactivity is shown in red. We performed the experiments as described in Nato et al. [21]. Scale bar 100 µm