FLT3 ligand regulates thymic precursor cells and hematopoietic stem cells through interactions with CXCR4 and the marrow niche

Abstract

Impaired immune reconstitution after hematopoietic stem cell transplantation (HSCT) is attributed in part to impaired thymopoiesis. Recent data suggest that precursor input may be a point of regulation for the thymus. We hypothesized that administration of FLT3 ligand (FLT3L) would enhance thymopoiesis after adoptive transfer of aged, FLT3L-treated bone marrow (BM) to aged, Lupron-treated hosts by increasing murine HSC (Lin^[minus]Sca1⁺c-Kit⁺ [LSK] cells) trafficking and survival. In murine models of aged and young hosts, we show that FLT3L enhances thymopoiesis in aged, Lupron-treated hosts through increased survival and export of LSK cells via CXCR4 regulation. In addition, we elucidate an underlying mechanism of FLT3L action on BM LSK cells-FLT3L drives LSK cells into the stromal niche using Hoescht (Ho) dye perimortem. In summary, we show that FLT3L administration leads to: (1) increased LSK cells and early thymocyte progenitor precursors that can enhance thymopoiesis after transplantation and androgen withdrawal, (2) mobilization of LSK cells through downregulation of CXCR4, (3) enhanced BM stem cell survival associated with Bcl-2 upregulation, and (4) BM stem cell enrichment through increased trafficking to the BM niche. Therefore, we show a mechanism by which FLT3L activity on hematopoeitic and thymic progenitor cells may contribute to thymic recovery. These data have potential clinical relevance to enhance thymic reconstitution after cytoreductive therapy.