Mesenchymal Stem Cells ameliorate Chronic GVHD by Boosting Thymic Regeneration in a CCR9-dependent manner in mice.

Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mature donor T cells within the graft contribute to severe damages on thymic epithelial cells (TECs), which is known as a key mediator in the continuum of acute graft-versus-host disease (aGVHD) and cGVHD pathology. Mesenchymal stromal cells (MSCs) are reported to be effective in the prevention and treatment of cGVHD. The incidence and severity of cGVHD in patients with refractory aGVHD after MSCs treatment were observed decrease in our previous pilot clinical trial, along with the increased levels of blood signal joint T cell receptor excision DNA circles (sjTRECs), which indicated an improvement in thymus function of GVHD recipients, but the mechanisms leading to these effects remain unknown. Here, we show in a murine GVHD model that MSCs promoted the quantity and maturity of thymic epithelial cells (TECs) as well as elevated the proportion of Aire+ medullary TECs, improving both CD4+CD8+ double-positive thymocytes and thymic Tregs, balancing CD4/CD8 ratio in blood. In addition, CCL25-CCR9 signaling axis was found to play an important role in guiding MSCs homing to thymus. These studies reveal mechanisms of MSCs ameliorate cGVHD by boosting thymic regeneration and offer innovative strategies for improving thymus function in GVHD recipients.