Tissue engineering human thymus from iPSCs to support human T cell development

Abstract

Abstract Thymus is the primary immune organ responsible for the generation of diverse and self-tolerant T cells that are essential for fighting off invading pathogens while maintaining immune homeostasis. Loss of thymus function, due to either genetic mutations or environmental insults, can lead to prolonged immunodeficiency that can be life-threatening. Rejuvenating the function of the thymus is challenging as the organ undergoes irreversible involution at young age, during which thymic epithelial cells (TECs) – the thymic stromal cells key to the education and selection of developing T cells – are progressively replaced by infiltrating adipocytes. Regeneration of thymus from the patient’s own stem cells will have tremendous clinical benefits in treating immunodeficiency and immunodysregulatory disorders. We reported here the tissue-engineering of functional artificial thymus from inducible pluripotent stem cells (iPSCs). Taking advantage of the 3D alginate encapsulation technology, we developed a novel protocol to induce the differentiation and maturation of human iPSCs into TECs (iPSC-TECs) at high efficiency. To bioengineer the thymus, iPSC-TECs were injected into decellularized murine thymus scaffolds, in conjunction with T cell progenitors derived from hematopoietic stem/progenitor cells (HSPCs) harvested from the umbilical cord blood. When transplanted under the kidney capsules of hematopoietic humanized mice (aka immunodeficient mice engrafted with HSPCs), iPSC-TEC thymus can support developed a diverse population of human T cells that could mediate adaptive immune responses. Our findings suggest that functional human thymus can be generated from patient-derived iPSCs for regenerative medicine. Supported in part by the NIH (R01 AI123392 and R21 AI126335), NSF (CBET 1804728), and Highmark Health Award (A023948-HIGHMARK-LANNI-FAN).