Stress and Non-Stress Roles of Inflammatory Signals during HSC Emergence and Maintenance

Abstract

Hematopoietic stem cells (HSCs) are a rare population that gives rise to almost all cells of the hematopoietic system, including immune cells. Until recently, it was thought that immune cells sense inflammatory signaling and HSCs respond only secondarily to these signals. However, it was later shown that adult HSCs could directly sense and respond to inflammatory signals, resulting in a higher output of immune cells. Recent studies demonstrated that inflammatory signaling is also vital for HSC ontogeny. These signals are thought to arise in the absence of pathogens, are active during development, and indispensable for HSC formation. In contrast, during times of stress and disease, inflammatory responses can be activated and can have devastating effects on HSCs. In this review, we summarize the current knowledge about inflammatory signaling in HSC development and maintenance, as well as the endogenous molecular cues that can trigger inflammatory pathway activation. Finally, we comment of the role of inflammatory signaling in hematopoietic diseases.

Hematopoietic Stem Cells but Not Multipotent Progenitors Drive Erythropoiesis during Chronic Erythroid Stress in EPO Transgenic Mice

“…All lineages of hematopoietic cells, including those of the erythroid lineage, arise from a unique population of hematopoietic stem cells (HSCs) ( Clapes et al., 2016 ). However, whether all mature blood cells are derived from these HSCs or from downstream multipotent progenitors (MPPs) during steady-state hematopoiesis remains contentious ( Busch et al., 2015 , Sawai et al., 2016 , Sun et al., 2014 ).…”

Identification of immune-activated hematopoietic stem cells

“…Importantly, expression changes may be uniform across all cells or heterogeneous at single-cell resolution. The latter alternative is of interest, as the HSC population is known to be functionally heterogeneous [ 14 ]. FACS analysis revealed an increase in CD317 and CD69 after acute pIC stimulation, confirming the RNA-Seq data to the protein level (Fig.…”

Cooperating, congenital neutropenia–associated Csf3r and Runx1 mutations activate pro-inflammatory signaling and inhibit myeloid differentiation of mouse HSPCs

“…Interestingly, mRNA expression analysis revealed that HSPCs harboring mutations in Csf3R and RUNX1 exhibit activation of the inflammatory and innate immunity pathways, including interferon signaling; IL-1, IL-6, IL-8, and TLR signaling; and TREM1 signaling. Additionally, we also found marked upregulation of Ly6a (also known as Sca-1), a marker of stemness in HSPCs [24] that is also upregulated upon inflammation [33][34][35]. IL-6 and IL-8 were previously known to be hyper-activated in MDS and AML [19,36,37].…”