Journal
BLOOD
Volume 140, Issue 14, Pages 1592-1606Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021014009
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Funding
- Sir Henry Dale fellowship from Wellcome/Royal Society [107630/Z/15/Z, 107630/Z/15/A]
- Medical Research Council (MRC) [203151/Z/16/Z]
- MRC [MR/M008975/1, 1942750]
- Wellcome [203151/Z/16/Z, 206328/Z/17/Z, RG74909]
- Blood Cancer UK [18002]
- Cancer Research UK [RG83389]
- William B Harrison Foundation [RG91681]
- Wellcome Trust [206328/Z/17/Z, 107630/Z/15/A] Funding Source: Wellcome Trust
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Adult hematopoietic stem cells (HSCs) respond to acute stress and STAT1 plays a pivotal role in regulating their function. STAT1-dependent functional HSC heterogeneity exists, highlighting the importance of understanding stem cell heterogeneity and its interaction with the immune system.
Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal downstream mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but little is known about the role of STAT1 in regulating homeostatic hematopoietic stem/progenitor cells (HSPCs). Here, we show that loss of STAT1 altered the steady state HSPC landscape, impaired HSC function in transplantation assays, delayed blood cell regeneration following myeloablation, and disrupted molecular programs that protect HSCs, including control of quiescence. Our results also reveal STAT1-dependent functional HSC heterogeneity. A previously unrecognized subset of homeostatic HSCs with elevated major histocompatibility complex class II (MHCII) expression (MHCIIhi) displayed molecular features of reduced cycling and apoptosis and was refractory to 5-fluorouracil-induced myeloablation. Conversely, MHCIIlo HSCs displayed increased megakaryocytic potential and were preferentially expanded in CALR mutant mice with thrombocytosis. Similar to mice, high MHCII expression is a feature of human HSCs residing in a deeper quiescent state. Our results therefore position STAT1 at the interface of stem cell heterogeneity and the interplay between stem cells and the adaptive immune system, areas of broad interest in the wider stem cell field.
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