MEGAKARYOCYTE-LINEAGE BIAS AND RESTRICTION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS

Abstract

Hematopoietic stem cells (HSCs), defined by long-term self-renewal and ability to replenish all blood lineages, are molecularly and functionally heterogeneous. This heterogeneity might have important implications in both steady-state and emergency hematopoiesis, as well as aging and hematological malignancies. We previously uncovered a highly organized framework of lineage-biased and lineage-restricted HSC fates through sensitive tracking of post-transplantation contribution of hundreds of single HSCs from adult murine bone marrow (BM) (Carrelha et al. Nature 2018). Most notably, we identified HSCs that in vivo contribute stably, effectively, and exclusively towards the megakaryocyte (Mk) branch of the hematopoietic tree, despite possessing multipotency. No long-term self-renewing HSCs contribute exclusively to any other lineage upon transplantation. We also identified Mk/erythroid/myeloid and Mk/erythroid/myeloid/B-cell restricted outputs. Contrary to previous studies, we found no evidence for long-term adult BM HSCs with sustained lymphoid bias. Recently we also performed single-cell transplantations of HSCs from late gestation mouse embryos (E19.5). We found that these fetal liver and fetal BM HSCs undergo almost exclusively multilineage fates, rarely producing lineage-restricted outputs, which suggests that the lineage biases and restrictions of adult HSCs are established in the BM postnatally. Through fate-mapping analysis with an inducible Vwf-Cre reporter we demonstrated that Mk-biased HSCs play an important role in unperturbed adult BM hematopoiesis. We have further observed that Mk-biased HSCs play a more prominent role in the rapid replenishment of platelets following an acute insult with 5-fluorouracil. In agreement with this data, single transplanted HSCs with Mk-restricted fate replenish platelets more rapidly than HSCs undergoing a multilineage fate.