Co-transplantation of tonsil-derived mesenchymal stromal cells in bone marrow transplantation promotes thymus regeneration and T cell diversity following cytotoxic conditioning

Abstract

Bone marrow (BM) transplantation (BMT) represents a curative treatment for various hematological disorders. Prior to BMT, a large amount of the relevant anticancer drug needed to be administered to eliminate cancer cells. However, during this pre-BMT cytotoxic conditioning regimen, hematopoietic stem cells in the BM and thymic epithelial cells were also destroyed. The T cell receptor (TCR) recognizes diverse pathogen, tumor and environmental antigens, and confers immunological memory and self-tolerance. Delayed thymus reconstitution following pre-BMT cytotoxic conditioning impedesde novothymopoiesis and limits T cell-mediated immunity. Several cytokines, such as RANK ligand, interleukin (IL)-7, IL-22 and stem cell factor, were recently reported to improve thymopoiesis and immune function following BMT. In the present study, it was found that the co-transplantation of tonsil-derived mesenchymal stromal cells (T-MSCs) with BM-derived cells (BMCs) accelerated the recovery of involuted thymuses in mice following partial pre-BMT conditioning with busulfan-cyclophosphamide treatment, possibly by inducing FMS-like tyrosine kinase 3 ligand (FLT3L) and fibroblast growth factor 7 (FGF7) production in T-MSCs. The co-transplantation of T-MSCs with BMCs also replenished the CD3(+)cell population by inhibiting thymocyte apoptosis following pre-BMT cytotoxic conditioning. Furthermore, T-MSC co-transplantation improved the recovery of the TCR repertoire and led to increased thymus-generated T cell diversity.