Bone marrow or stem cell transplantation
Adaptive T cell immunity and central tolerance are fundamental functions of the human immune system and constitute the core of anti-infectious host defense, cancer surveillance and self-tolerance. Compromise manifests in infection, autoimmunity, malignancy and transplant complications. Adaptive T cell immunity and central tolerance are developed in the thymus. Untreated congenital absence of the thymus is not compatible with life and acquired thymic injury can lead to infections and autoimmunity. For all these conditions, therapies are lacking, making regenerative thymic tissues a critically unmet clinical need.
Despite promising reports of in vitrohuman thymopoiesis, these efforts have not translated into the production of clinically relevant engineered thymic tissues. We seek to make functional thymic epithelia from induced pluripotent stem cells (iPSCs) and leverages new technologies to address prior limitations. First, we elucidate the cell-cell signals governing thymic ontogeny by dissecting signaling pathways in human fetal thymus using single-cell RNA sequencing. Second, we employ genomic, proteomic, immunohistochemistry, and non-linear imaging methods to map the extracellular matrix (ECM) chemistry and design a customizable, engineered ECM to support 3D culture of TECs. Third, we will recapitulate critical cell-cell and cell-matrix signals necessary to differentiate human iPSCs into functional thymic epithelial cells and mimic the dynamic regulation of endogenous transcription using synthetic biology approaches. These three orthogonal strategies will be pursued in parallel, ultimately converging in the development of an iPSC-derived, functional thymic epithelial organoid embedded within a biologically active 3D matrix for direct transplantation.