Figure 1.

Mechanisms regulating HSPC activity in the spleen. Schematic representation of the HSPC behavior during splenic myelopoiesis, showing multiple cell types and factors of various origins that directly or indirectly regulate HSPC activity. The splenic HSPC response is initiated with (1) increased production of chemokines, such as SDF-1 and CCL2, by endothelial cells and stromal cells around sinusoids. This change of chemokine production might be triggered by systemic factors that convey organismal stress messages. (2) HSPC survival is supported with the key niche-derived cytokine SCF and HSPCs express CD47 to avoid being engulfed by splenic macrophages. In addition, HSPCs express VLA-4 and downregulate S1P1 to maintain in the splenic niche. (3) Activated by systemic, niche-derived, and neural signals, splenic HSPCs upregulate transcription factors including RORC1/RORγ and C/EBPβ to direct myeloid-biased differentiation. Emerging evidence highlights the roles of the HSPC endogenous cytokines such as GM-CSF, and the transcription factor NF-κB that drives the production of cytokines in HSPC, as key regulators of HSPC behavior. (4) HSPCs proliferate and differentiate into different myeloid cell populations to respond to the body's or, unfortunately, the tumor's call. AGTE1A, type1A angiotensin II receptor; AngII, angiotensin II; C/EBPβ, CCAAT/enhancer-binding protein β; CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif chemokine receptor 5; CXCR4, C-X-C motif chemokine receptor 4; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; RORγ, related orphan receptor γ; S1P1, sphingosine-1-phosphate receptor 1; SCF, stem cell factor; SDF-1, stromal-cell-derived factor-1; SIRPα, signal regulatory protein α; Tlx1, T-cell leukemia homeobox protein 1; VCAM-1, vascular cell adhesion molecule-1; VLA4, very late antigen-4.