Cytotoxic and Genotoxic Stress Transiently Increase the Contribution of Platelet-Biased Hematopoietic Stem Cells to Platelet Production.

Platelets are produced via a canonical pathway emanating from multilineage hematopoietic stem cells (ML-HSCs) and a faster, direct pathway used by platelet-biased (P-) HSCs where the latter circumvents progenitors intermediate between HSCs and megakaryocytes. However, the physiological role of these distinct pathways remains to be determined. Here, we use Vldlr-iCre lineage tracing to identify platelets originating from platelet-biased HSCs and to show that P-HSC contribution to the megakaryocyte progenitor (MkP) population and platelet production is increased after 5-fluorouracil or cyclophosphamide treatment, where proliferating progenitors are severely depleted. In contrast, antibody-mediated platelet depletion, which leaves the progenitor hierarchy intact, did not increase the proportion of platelets generated by P-HSCs. Therefore, P-HSCs provide rapid platelet reconstitution without the need for complete re-establishment of the progenitor hierarchy after cytotoxic and genotoxic challenges due to their ability to more rapidly generate megakaryocyte progenitors from HSCs.