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

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 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.

IRF1 regulates self-renewal and stress-responsiveness to support hematopoietic stem cell maintenance

“…This interaction was further suggested to control differentiation and elimination of aberrant HSPCs. A later report revealed that MHC-II low WT HSCs were more apoptotic and responsive to 5-FU- and pI:pC-induced proliferation 50 . We found that Irf1 -/- HSCs exhibited reduced MHC-II expression and increased LPS-induced proliferation, suggesting that the latter feature may be controlled by an MHC-II-mediated mechanism.…”

“…Finally, our transcriptional profiling had demonstrated decreased expression of genes involved in antigen presentation and processing in Irf1 -/- HSCs, including MHC class II genes H2-Eb1, H2-Ab1, H2-Aa, H2-Q6, H2-DMa and known controllers of MHC-II expression – Ciita and Stat1 (Supplementary Table 1, Supplementary Figure 6). MHC-II expression was recently linked to HSC functionality 49, 50 , which prompted us to evaluate cell surface MHC-II expression on Irf1 -/- HSCs . We observed a striking 10.5-fold reduction in MHC-II on Irf1 -/- HSCs (Figure 5D and E), suggesting that MHC-II may play a role in altered Irf1 -/- HSC function.…”

“…We found that Irf1 -/- HSCs exhibited reduced MHC-II expression and increased LPS-induced proliferation, suggesting that the latter feature may be controlled by an MHC-II-mediated mechanism. Moreover, loss of the direct IRF1 target STAT1 22 in Irf1 -/- HSCs may account for the reduced MHC-II expression and impaired repopulation activity 50 . Loss of MHC-II promotes immune evasion 55 resulting in decreased elimination of leukemic cells 49 .…”

YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations

“…Beyond this dysregulation, a variety of functionally similar genes associated with cancer progression were identified as upregulated in BAP1 KO MeT‐5A cells. This includes STAT1 and STAT3 , which encode two STAT family transcription factors, both of which are involved in the maintenance of healthy and cancer stem cells, 93,94 while STAT3 additionally has been proposed as a target for treatment in PM 95 . PDGFA and VEGFA , which both code for mitogenic growth factors known to stimulate mesenchymal proliferation associated with tumorigenesis are additionally upregulated in BAP1 KO cells 96 .…”

Basal type I interferon signaling has only modest effects on neonatal and juvenile hematopoiesis

“…14 This finding aligns with recent observations in adult mice showing that Stat1 deletion causes a reduction of MPP numbers. 10, 15 However, Ifnar1 -deficient mice develop normally, despite the aforementioned transcriptional changes, suggesting that the loss of phenotypic MPPs does not markedly impair hematopoiesis. Assessments of HSC and MPP frequencies by flow cytometry are confounded by the fact that Sca1, an HSC/MPP surface marker, is itself positively regulated by IFN-1.…”