Patient-specific induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine therapies, theoretically allowing for the creation of autologous replacement tissues devoid of many of the immunogenic properties that hinder modern allogeneic organ transplants. However, recent studies have raised questions as to whether iPSC-derived tissues will indeed be tolerated by the autologous immune system or if these differentiated tissues will elicit an immune response detrimental to engraftment and/or graft function. Humanized mouse models offer a tractable in vivo system to experimentally test immunological hypothesizes and therapeutic interventions in the context of a human immune system. In the work presented here, we explore the development of a novel humanized mouse model incorporating cryopreserved human pediatric thymus tissue, umbilical cord blood (UCB) hematopoietic stem cells (HSCs) and iPSCs derived from the thymus donor. This system has the potential for comprehensive analysis of the patient immune repertoire's interaction with autologous and allogeneic iPSC-derived tissues. Further, we hypothesize that the more developmentally mature pediatric thymus and UCB HSCs (compared to fetal thymus and fetal liver HSCs, respectively) will yield a more adult-like distribution of regulatory T cells in the animals. This in turn may afford a more representative model of clinical patient immune responses.

We have derived primary thymic stromal cell lines from the thymus donors and successfully reprogrammed them into iPSCs using defined culture conditions and non-integrating reprogramming methods. In our humanized mouse experiments seeking to validate the use of pediatric thymus and UCB HSCs compared to conventional fetal controls, the animals demonstrate clear engraftment of the pediatric thymus tissue and go on to develop a T cell repertoire in an MHC-restricted manner strongly influenced by the haplotype of the thymus tissue. These data indicate that the pediatric tissue/UCB model is comparable to fetal tissue control animals and may prove useful for downstream experiments to determine the immunogenicity of iPSC-derived tissue.

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