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 multi-lineage 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. Teaser Abstract: The study shows that platelet-biased hematopoietic stem cells (P-HSCs) provide a rapid pathway for platelet production that bypasses intermediate progenitors. Using a Vldlr-iCre lineage-tracing mouse model, the authors demonstrate that this direct pathway becomes significantly more active after cytotoxic or genotoxic stress (e.g., 5-FU or cyclophosphamide), when platelet progenitors are depleted. In contrast, simple platelet depletion without progenitor damage does not increase P-HSC contribution. Thus, P-HSCs accelerate platelet recovery after stress by rapidly generating megakaryocyte progenitors, supporting a specialized physiological role in emergency thrombopoiesis.