Developmental cues license emergency megakaryopoiesis in hematopoietic stem cells [scATAC-seq]

The fetal to adult switch in mouse hematopoietic stem cell (HSC) behavior is characterized by entry into quiescence and alterations in lineage output. Here we identify the ability of HSCs to undergo emergency megakaryopoiesis following acute inflammatory insult as an outcome of this developmental switch. Single cell accessibility mapping of fetal and adult HSCs resolves a heterogeneous chromatin landscape consistent with a two-step megakaryocyte lineage priming process. Importantly, we demonstrate that the accumulation of megakaryocyte primed HSCs is under the control of the developmentally restricted Lin28b RNA binding protein. Persistent Lin28b protein expression in postnatal HSCs delays the formation of a primed HSC pool and limits emergency megakaryopoiesis. Taken together, we identify Lin28b as a negative regulator of a megakaryocyte primed HSC state that is enforced at the chromatin level during unperturbed organismal development. These findings highlight the ontogenically timed onset of inflammatory responsiveness, with important implications for the delicate balance between host protection and tissue damage during neonatal life. Overall design: Single cell ATAC-seq was used to compare megakaryocyte priming between E14.5 fetal liver and adult bone marrow hematopoietic stem cells. FL CD41- HSC: CD3-Gr1-B220-ter119-7AAD-cKit+Sca1+CD48-CD150+Flt3-CD41-, ABM CD41- HSC: CD3-Gr1-B220-ter119-CD11b-7AAD-cKit+Sca1+CD48-CD150+Flt3-CD41-, ABM CD41int HSC: CD3-Gr1-B220-ter119-CD11b-7AAD-cKit+Sca1+CD48-CD150+Flt3-CD41+, ABM MkP: :CD3-Gr1-B220-ter119-CD11b-7AAD-cKit+Sca1-CD150+CD41+.