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

TY - JOUR

T1 - STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resists myeloablation and neoplastic expansion

AU - Li, Juan

AU - Williams, Matthew Joseph

AU - Park, Hyun Jung

AU - Bastos, Hugo P

AU - Wang, Xiaonan

AU - Prins, Daniel Prins

AU - Wilson, Nicola K

AU - Johnson, Carys

AU - Sham, Kendig

AU - Wantoch, Michelle

AU - Watcham, Sam

AU - Kinston, Sarah Jane

AU - Pask, Dean C

AU - Hamilton, Tina L

AU - Sneade, Rachel

AU - Waller, Amie Karen

AU - Ghevaert, Cedric

AU - Vassiliou, George S

AU - Laurenti, Elisa

AU - Kent, David G

AU - Gottgens, Bertie

AU - Green, Anthony R

N1 - © 2022 American Society of Hematology.

PY - 2022/6/29

Y1 - 2022/6/29

N2 - 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 which protect HSCs including control of quiescence. Our results also reveal STAT1-dependent functional HSC heterogeneity. A previously unrecognized subset of homeostatic HSCs with elevated MHCII expression (MHCIIhi) displayed molecular features of reduced cycling and apoptosis, and was refractory to 5-FU 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.

AB - 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 which protect HSCs including control of quiescence. Our results also reveal STAT1-dependent functional HSC heterogeneity. A previously unrecognized subset of homeostatic HSCs with elevated MHCII expression (MHCIIhi) displayed molecular features of reduced cycling and apoptosis, and was refractory to 5-FU 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.

U2 - 10.1182/blood.2021014009

DO - 10.1182/blood.2021014009

M3 - Article

C2 - 35767701

JO - Blood

JF - Blood

SN - 0006-4971

ER -