STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resist myeloablation and neoplastic expansion.
Juan LiMatthew J WilliamsHyun Jung ParkHugo P BastosXiaonan WangDaniel PrinsNicola K WilsonCarys JohnsonKendig ShamMichelle WantochSam WatchamSarah J KinstonDean C PaskTina L HamiltonRachel SneadeAmie K WallerCedric GhevaertGeorge S VassiliouElisa LaurentiDavid G KentBerthold GöttgensAnthony R GreenPublished in: Blood (2022)
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.
Keyphrases
- stem cells
- single cell
- cell therapy
- cell proliferation
- poor prognosis
- dendritic cells
- high glucose
- endothelial cells
- drug induced
- bone marrow
- diabetic rats
- signaling pathway
- liver failure
- public health
- endoplasmic reticulum stress
- intensive care unit
- high fat diet induced
- deep learning
- insulin resistance
- adipose tissue
- single molecule
- mesenchymal stem cells
- long non coding rna
- hepatitis b virus
- wild type
- african american
- mechanical ventilation
- risk assessment
- young adults