Abstract
Abstract Myeloid differentiation protein 88 (MyD88) is an adaptor protein that is required for signaling through most Toll-like receptors (TLRs) as well as the IL-1R family. While these pathways are primarily considered in cells of the innate immune system, TLRs are also expressed by hematopoietic stem cells (HSCs) and progenitor cells. We sought to examine the potential importance of MyD88 during hematopoietic development. We find that bone marrow from WT and Myd88-/- C57BL/6 mice contains comparable numbers of HSCs, which give rise to differentiated progenitors with equivalent efficiency in vitro. However, following a competitive mixed bone marrow transplant (BMT) into lethally irradiated recipients, WT HSCs display a significant advantage over Myd88-/- HSCs, resulting in a stable predominance of WT-derived cells in the reconstituted myeloid and lymphoid compartments. This skewed ratio of mature WT to Myd88-/- cells in the periphery of reconstituted mice is apparent in all developmental stages including the earliest long term HSCs. Interestingly, we find that WT HSCs do not exhibit this advantage over Myd88-/- HSCs following competitive BMT into non-irradiated recipients. Overall, our data suggest that factors associated with irradiation, such as inflammation, act on HSCs in a MyD88-dependent fashion to promote long-term engraftment of transplanted bone marrow.
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