STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resist myeloablation and neoplastic expansion

Author:

Li Juan12,Williams Matthew J.12,Park Hyun Jung12,Bastos Hugo P.12ORCID,Wang Xiaonan12ORCID,Prins Daniel12,Wilson Nicola K.12ORCID,Johnson Carys12,Sham Kendig12,Wantoch Michelle12,Watcham Sam12,Kinston Sarah J.12,Pask Dean C.12,Hamilton Tina L.12,Sneade Rachel12,Waller Amie K.12,Ghevaert Cedric12,Vassiliou George S.12ORCID,Laurenti Elisa12ORCID,Kent David G.3ORCID,Göttgens Berthold12,Green Anthony R.12

Affiliation:

1. 1Wellcome–Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge, United Kingdom

2. 2Department of Haematology, University of Cambridge, Cambridge, United Kingdom

3. 3Department of Biology, University of York, York, United Kingdom

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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