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Teratoma formation by Safe and Allo-Accepted Pluripotent Cells

ABSTRACT: Pluripotent stem cells are a promising alternative in cell and tissue transplantation as they have the potential to be differentiated into different cell types to treat various diseases. However, two major challenges have hindered their clinical application: concerns associated with risk of allogeneic rejection, in addition to safety issues related to uncontrolled proliferation and tumorigenicity. In this study, we utilised the H1 ESC line that was engineered to possess immune-evading properties to avoid rejection, and equipped with a "SafeCell" kill switch to selectively kill aberrantly proliferating cells. We used a humanised mouse model to demonstrate the successful generation of allogeneic tissues from SafeCell-AlloAccept (SC-AlloAccept) cells transplanted in the immune-active subcutaneous region of immunocompetent humanised mice. These cells formed teratomas and their growth was controlled with pro-drug ganciclovir that activated the kill switch, which successfully eliminated proliferating cells, rendering the remaining tissue dormant. This SC-AlloAccept-derived graft was harvested at 108 days post transplantation, highlighting their potential for long-term engraftment without rejection. We also showed that neither prior rejection of immunogenic parental H1 cells (sensitization) nor the presence of SC-AlloAccept tissue (potential immune compromise) affected the immune response to a subsequent, second transplant. This study validates the application of safe and AlloAccept human cells in transplantation, providing important insights into the immune status of the naive and sensitised human immune system of the host in a mouse model. These findings mark a key step towards the application of stem cells that can be universally accepted, towards cell-based regenerative therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319407 | GEO | 2026/02/25

REPOSITORIES: GEO

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Project description:Immune privileged Sertoli cells (SC) survive when transplanted across immunological barriers and prolong the survival of co-transplanted allogeneic and xenogeneic cells in rodent models. However, the mechanism for this survival and protection remains unresolved. We have recently identified a mouse Sertoli cell line (MSC-1) that lacks some of the immunoprotective abilities associated with primary SC. The objective of this study was to compare the survival and gene expression profiles of primary SC and MSC-1 cells to identify factors or immune-related pathways potentially important for SC immune privilege. Primary SC or MSC-1 cells were transplanted as allografts to the renal subcapsular area of naïve BALB/c mice and cell survival was analyzed by immunohistochemistry. Additionally, transcriptome differences were investigated by microarray and pathway analyses. While primary SC were detected within the grafts with 100% graft survival throughout the 20-day study, MSC-1 cells w ere rejected between 11 and 14 days with 0% graft survival at 20 days post-transplantation. Microarray analysis identified 3198 genes that were differentially expressed with a ± 4-fold or higher level in primary SC. Cluster and pathway analyses indicate that the mechanism of SC immune privilege is likely complex with multiple immune modulators being involved such as immunosuppressive cytokines and complement inhibitors, lipid mediators for controlling inflammation, and junctional molecules that control leukocyte movement in and out of the immune privileged space. Further study of these immune modulators will increase our understanding of SC immune privilege and in the long-term lead to improvements in transplantation success. We conducted microarray and pathway analyses to identify genes and immune-related pathways differentially regulated by aggregated primary Sertoli cells and MSC-1 cell line. Aggregated 19 to 20-day mice primary Sertoli cells and MSC-1 cell line were used to determine the global transcriptome differences important for the survival and protection of transplanted cells.

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Teratoma formation by Safe and Allo-Accepted Pluripotent Cells

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