Transplantation of Donor‐Origin Mouse Embryonic Stem Cell‐Derived Thymic Epithelial Progenitors Prevents the Development of Chronic Graft‐versus‐Host Disease in Mice

: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many malignant and nonmalignant diseases. However, chronic graft-versus-host disease (cGVHD) remains a significant cause of late morbidity and mortality after allogeneic HSCT. cGVHD often manifests as autoimmune syndrome. Thymic epithelial cells (TECs) play a critical role in supporting negative selection and regulatory T-cell (Treg) generation. Studies have shown that damage in TECs is sufficient to induce cGVHD. We have previously reported that mouse embryonic stem cells (mESCs) can be selectively induced to generate thymic epithelial progenitors (TEPs) in vitro. When transplanted in vivo, mESC-TEPs further develop into TECs that support T-cell development. We show here that transplantation of donor-origin mESC-TEPs into cGVHD recipients induces immune tolerance to both donor and host antigens and prevents the development of cGVHD. This is associated with more TECs and Tregs. Our results suggest that embryonic stem cell-derived TEPs may offer a new tool to control cGVHD. SIGNIFICANCE Allogeneic hematopoietic stem cell transplantation (HSCT) is widely used in the treatment of many malignant and nonmalignant diseases. However, chronic graft-versus-host disease (cGVHD) remains a significant cause of late morbidity and mortality following allogeneic HSCT. This study shows that transplantation of mouse embryonic stem cell (ESC)-derived thymic epithelial progenitors (TEPs) into cGVHD recipient mice prevents the development of cGVHD. Results suggest that generation of TEPs from human ESCs have the potential to provide a novel approach to prevent the development of cGVHD in patients after allogeneic HSCT.