Abstract
The safe utilization of induced pluripotent stem cell (iPSC) derivatives in clinical use is attributed to the complete elimination of the risk of forming teratomas after transplantation. The extent by which such a risk exists in immune-competent hosts is mostly unknown. Here, using humanized mice reconstituted with fetal hematopoietic stem cells and autologous thymus tissue (bone–liver–thymus humanized mice [Hu-BLT]) or following the adoptive transfer of peripheral blood mononuclear cells(PBMCs) (Hu-AT), we evaluated the capacity of immune cells to prevent or eliminate teratomas derived from human iPSCs (hiPSCs). Our results showed that the injection of hiPSCs failed to form teratomas in Hu-AT mice reconstituted with allogeneic or autologous PBMCs or purified natural killer (NK) cells alone. However, teratomas were observed in Hu-AT mice reconstituted with autologous PBMCs depleted from NK cells. In line with these results, Hu-BLT, which do not have functional NK cells, could not prevent the growth of teratomas. Finally, we found that established teratomas were not targeted by NK cells and instead were efficiently rejected by allogeneic but not autologous T cells in Hu-AT mice. Overall, our findings suggest that autologous hiPSC-derived therapies are unlikely to form teratomas in the presence of NK cells.
Highlights
The potential of regenerative medicine is greatly enhanced by the development of induced pluripotent stem cells
We used two different models of humanized mice: (i) Hu-bone–liver–thymus (BLT) mice generated by the co-transplantation of fetal liver hematopoietic stem cells along with autologous human thymus tissues that allow for the development and maturation of competent human T cells and (ii) Hu-AT mice reconstituted following the adoptive transfer (AT) of adult peripheral blood mononuclear cells (PBMCs); and we demonstrated that teratoma formation by human induced pluripotent stem cells (iPSCs) (hiPSCs) is abolished only in the presence of natural killer (NK) cells and that this NK-specific cytotoxicity is lost upon the differentiation of hiPSCs
To investigate if immune cells could protect against the formation of hiPSC-derived teratomas, we first generated hiPSC clones from skin fibroblasts or PBMCs collected from different donors using an integration-free (Sendai virus) approach
Summary
The potential of regenerative medicine is greatly enhanced by the development of induced pluripotent stem cells (iPSCs). The injection of only a few hundred human embryonic cells was sufficient to form a teratoma in immunodeficient mice [1]. The need for pluripotent stem cells to evade immune responses may be required for the growth of teratomas in vivo. Immunogenicity of iPSCs in Humanized Mice form teratomas when injected subcutaneously in syngeneic recipients [4]. A response they showed was dependent on the abnormal overexpression of immunogenic genes in iPSCs and on the presence of antigen-presenting cells at the injection site [4, 5]. The pioneering work by Dressel et al showed that mouse iPSCs can give rise to teratomas in autologous/syngeneic mice in the absence of the activation of the host natural killer (NK) cells [6, 7]. We used two different models of humanized mice: (i) Hu-bone–liver–thymus (BLT) mice generated by the co-transplantation of fetal liver hematopoietic stem cells along with autologous human thymus tissues that allow for the development and maturation of competent human T cells and (ii) Hu-AT mice reconstituted following the adoptive transfer (AT) of adult peripheral blood mononuclear cells (PBMCs); and we demonstrated that teratoma formation by hiPSCs is abolished only in the presence of NK cells and that this NK-specific cytotoxicity is lost upon the differentiation of hiPSCs
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