Developmental cues license megakaryocyte priming in murine hematopoietic stem cells

The fetal-to-adult switch in hematopoietic stem cell (HSC) behavior is characterized by alterations in lineage output and entry into deep quiescence. Here we identify the emergence of megakaryocyte (Mk)-biased HSCs as an event coinciding with this developmental switch. Single-cell chromatin accessibility analysis reveals a ubiquitous acquisition of Mk lineage priming signatures in HSCs during the fetal-to-adult transition. These molecular changes functionally coincide with increased amplitude of early Mk differentiation events after acute inflammatory insult. Importantly, we identify LIN28B, known for its role in promoting fetal-like self-renewal, as an insulator against the establishment of an Mk-biased HSC pool. LIN28B protein is developmentally silenced in the third week of life, and its prolonged expression delays emergency platelet output in young adult mice. We propose that developmental regulation of Mk priming may represent a switch for HSCs to toggle between prioritizing self-renewal in the fetus and increased host protection in postnatal life.

Automated summary

The fetal-to-adult switch in hematopoietic stem cell behavior is characterized by changes in lineage output and entry into deep quiescence. The emergence of megakaryocyte-biased HSCs coincides with this developmental switch. Molecular changes in HSCs during the fetal-to-adult transition include acquisition of megakaryocyte lineage priming signatures and increased amplitude of early megakaryocyte differentiation events. LIN28B, which promotes fetal-like self-renewal, acts as an insulator against the establishment of a megakaryocyte-biased HSC pool. The developmental regulation of megakaryocyte priming may represent a switch for HSCs to prioritize self-renewal in the fetus and increased host protection in postnatal life.