Abstract
The transcription factor PU.1 is a critical regulator of lineage fate in blood-forming hematopoietic stem cells (HSC). In response to pro-inflammatory signals, such as the cytokine IL-1β, PU.1 expression is increased in HSC and is associated with myeloid lineage expansion. To address potential functional heterogeneities arising in the phenotypic HSC compartment due to changes in PU.1 expression, here, we fractionated phenotypic HSC in mice using the SLAM surface marker code in conjunction with PU.1 expression levels, using the PU.1-EYFP reporter mouse strain. While PU.1lo SLAM cells contain extensive long-term repopulating activity and a molecular signature corresponding to HSC activity at steady state, following IL-1β treatment, HSCLT induce PU.1 expression and are replaced in the PU.1lo SLAM fraction by CD41+ HSC-like megakaryocytic progenitors (SL-MkP) with limited long-term engraftment capacity. On the other hand, the PU.1hi SLAM fraction exhibits extensive myeloid lineage priming and clonogenic activity and expands rapidly in response to IL-1β. Furthermore, we show that EPCR expression, but not CD150 expression, can distinguish HSCLT and SL-MkP under inflammatory conditions. Altogether, our data provide insights into the dynamic regulation of PU.1 and identify how PU.1 levels are linked to HSC fate in steady state and inflammatory stress conditions.
Highlights
Blood system responses to physiological stress require a coordinated and dynamic re-balancing of hematopoietic stem cell (HSC) fate to meet changes in demand for specific blood lineages while preserving long-term HSC function and lifelong blood system maintenance [1]
We previously showed that chronic IL-1β treatment increases PU.1 levels in HSC and is associated with precocious myeloid differentiation [3]
We show that PU.1 expression levels are linked to distinct cell fate outcomes, long-term reconstitution capacity and lineage output
Summary
Blood system responses to physiological stress require a coordinated and dynamic re-balancing of hematopoietic stem cell (HSC) fate to meet changes in demand for specific blood lineages while preserving long-term HSC function and lifelong blood system maintenance [1]. HSC themselves have been shown to express very low levels of PU., which is associated with homeostatic blood lineage output and normal self-renewal function [10,13,14]. We found that increased PU. expression in long-term HSC (HSCLT ) rapidly engages a quiescence-enforcing program that represses protein synthesis and cell cycle genes, thereby preventing spurious proliferation and maintaining HSC pool size in response to inflammatory stress [7]. PU. appears to modulate multiple fate choices that impact blood production in response to inflammatory stress
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