Abstract

Cord blood hematopoietic stem/progenitor cells (CB-HSPCs) have emerged as a promising supply for functional platelets to potentially alleviate the increasing demand for platelet transfusions, but the clinical application has been limited by the undefined molecular mechanism and insufficient platelet production. Here, we performed single-cell profiling of more than 16?160 cells to construct a dynamic molecular landscape of human megakaryopoiesis from CB-HSPCs, enabling us to uncover, for the first time, cellular heterogeneity and unique features of neonatal megakaryocytes (MKs) and to also offer unique resources for the scientific community. By using this model, we defined the genetic programs underlying the differentiation process from megakaryocyte-erythroid progenitors (MEPs) to MKs via megakaryocyte progenitors (MKPs) and identified inhibitors of euchromatic histone lysine methyltransferase (EHMT), which, when applied at the early stage of differentiation, significantly increase the final platelet production. At the mechanistic level, we found that EHMT inhibitors act to selectively induce the expansion of MEPs and MKPs. Together, we uncover new mechanistic insights into human megakaryopoiesis and provide a novel chemical strategy for future large-scale generation and clinical applications of platelets.