STEM CELL LIKE ERYTHROID/MEGAKARYOCYTE-PRIMED PROGENITORS EXPAND IN HUMANS IN RESPONSE TO FREQUENT PLATELET DONATION

Blood formation is maintained by a heterogeneous pool of haematopoietic stem cells and multipotent progenitors (HSC/MPPs), consisting of subsets with distinct functional behaviours and molecular make-ups. However, the contribution of different HSC subsets to adult human blood production and to the altered haematopoietic phenotypes associated with stress or disease remains unexplored. Here, we study the composition of the adult human HSC pool from the peripheral blood (PB) of healthy frequent platelet donors. We find that human phenotypic PB HSC/MPPs display heterogeneous differentiation potential in single-cell culture assays and a rare subset has long-term repopulation capacity in xenograft models. Unexpectedly a large fraction of single HSC/MPPs exclusively commits to the erythroid/megakaryocytic (Ery/Mk) lineage in vitro. These cells, which we termed “stem cell like Ery/Mk-primed progenitors” (SL-EMPPs), can be prospectively purified from phenotypic HSC/MPPs as CD71+ CD34lo and do not engraft NSG mice. Similar to multipotent HSCs, SL-EMPPs are largely quiescent, but display gene signatures indicative of increased metabolic activity. Yet, SL-EMPPs also substantially differ from classical Ery/Mk progenitors as for cell cycle status, signalling pathway activity and serial replating capacity. Strikingly, SL-EMPPs are extremely rare in haematopoietic tissues from non-platelet donors including steady-state PB, indicating an expansion of this subset in response to frequent platelet donation. Interestingly, SL-EMPPs were also detected in PB of patients with essential thrombocythemia, a disease characterised by overproduction of platelets, suggesting a potential contribution of SL-EMPPs to blood disorders. In conclusion, our results identify the cellular route by which, in humans, stress-induced chronic platelet overproduction is mediated directly from the HSC compartment.