Developmental cues license megakaryocyte priming in murine hematopoietic stem cells

Abstract

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 an increased amplitude of early Mk differentiation events following acute inflammatory insult. Importantly, we identify LIN28B - known for its role in promoting fetal-like self-renewal, as an insulator against the establishment of a 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.

Enhanced protein synthesis is a defining requirement for neonatal B cell development

“…Endogenous LIN28B expression is developmentally limited to fetal and neonatal life. FACS analysis of LIN28B-eGFP reporter mice (34) captured its window of expression in B cell precursors as it gradually diminished to background levels after day 10 (Figure 4A). Following the same kinetics, neonatal B cell development exhibits a transient elevation of protein synthesis rates as measured by AHA uptake (Figure 4B).…”

“…Wildtype mice were originally purchased from Taconic (B6NTAC, Taconic). The Lin28b -eGFP knock-in strain was generated as previously described (34). Adult mice were used at 10 to 16 weeks of age, neonates were analyzed at the indicated days post-birth.…”

“…Endogenous LIN28B expression is developmentally restricted. FACS analysis of LIN28B-eGFP reporter mice (34) captured its window of expression as eGFP gradually diminished to background levels after postnatal day 10 in B cell precursors and postnatal day 19 in hematopoietic stem and progenitor cells (HSPCs) (Figure 4A). This time-window correlates with the output of B-1a cells which ceases between day 10 and day 19 during unperturbed hematopoiesis (45).…”

Occurrence and role of lung megakaryocytes in infection and inflammation

“…The production of platelets from MK-biased hematopoietic progenitors is observed preferentially after reduced platelet count (5), inflammation, myeloproliferative neoplasms, aging, and recently, respiratory viral infection (6), also called "emergency" megakaryopoiesis and reviewed by Noetzli et al (7) (Figure 1). Mechanistically, MK-biased HSC is posttranscriptionally regulated by the repression of MK-specific transcript translation steady state (8) and before birth (9). The restriction, maintained by the RNA-binding protein LIN28B, is lifted during development or inflammatory stress by the downregulation of the protein, leading to the increase of MK-biased HSCs.…”

“…( 7 ) ( Figure 1 ). Mechanistically, MK-biased HSC is posttranscriptionally regulated by the repression of MK-specific transcript translation steady state ( 8 ) and before birth ( 9 ). The restriction, maintained by the RNA-binding protein LIN28B, is lifted during development or inflammatory stress by the downregulation of the protein, leading to the increase of MK-biased HSCs.…”