Fate decision of haematopoietic stem cells determined by differential cytokine niches

　Arterioles and sinusoids of the bone marrow (BM) are accompanied with distinct stromal cells marked by nerve/glial antigen 2 (NG2) and leptin receptor (LepR), conferring specialised niches regulating quiescence and proliferation of haematopoietic stem cells (HSCs). However, it remains unknown how distinct niche cells differentially regulate HSC functions. Here, we show that the effects of cytokines regulating HSC functions are dependent on the producing cell sources. Deletion of chemokine C-X-C motif ligand 12 (Cxcl12) or stem cell factor (Scf) from all perivascular cells marked by Nestin-GFP dramatically depleted BM HSCs. Selective Cxcl12 deletion from arteriolar NG2+ cells, but not from sinusoidal LepR+ cells, caused significant HSC reductions and altered HSC localisation in BM. By contrast, deletion of Scf in LepR+ cells, but not NG2+ cells, led to significant reductions in BM HSC numbers. These results uncover distinct contributions of cytokines derived from perivascular cells in separate vascular niches for HSC maintenance.

　RNA-seq analysis of peri-vascular niche cells. Heatmap of unsupervised hierarchical clustering of significant enriched genes.

　Proposed model of HSC regulation by distinct perivascular niche cells (NG2 and LepR positive mesenchymal stem cells) via different cytokines (CXCL12 and SCF).