CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age

The hematopoietic stem cell (HSC) compartment is heterogeneous, yet our understanding of the identities of different HSC subtypes is limited. Here we show that platelet integrin CD41 (αIIb), currently thought to only transiently mark fetal HSCs, is expressed on an adult HSC subtype that accumulates with age. CD41+ HSCs were largely quiescent and exhibited myeloerythroid and megakaryocyte gene priming, governed by Gata1, whereas CD41- HSCs were more proliferative and exhibited lymphoid gene priming. When isolated without the use of blocking antibodies, CD41+ HSCs possessed long-term repopulation capacity on serial transplantations and showed a marked myeloid bias compared with CD41- HSCs, which yielded a more lymphoid-biased progeny. CD41-knockout (KO) mice displayed multilineage hematopoietic defects coupled with decreased quiescence and survival of HSCs, suggesting that CD41 is functionally relevant for HSC maintenance and hematopoietic homeostasis. Transplantation experiments indicated that CD41-KO-associated defects are long-term transplantable, HSC-derived and, in part, mediated through the loss of platelet mass leading to decreases in HSC exposure to important platelet released cytokines, such as transforming growth factor β1. In summary, our data provide a novel marker to identify a myeloid-biased HSC subtype that becomes prevalent with age and highlights the dogma of HSC regulation by their progeny.