Differential cytokine contributions of perivascular haematopoietic stem cell niches

Abstract

Arterioles and sinusoids of the bone marrow (BM) are accompanied by stromal cells that express nerve/glial antigen 2 (NG2) and leptin receptor (LepR), and constitute specialised niches that regulate quiescence and proliferation of haematopoietic stem cells (HSCs). However, how niche cells differentially regulate HSC functions remains unknown. 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 HSC reductions and altered HSC localisation in BM. By contrast, deletion of Scf in LepR+ cells, but not NG2+ cells, led to reductions in BM HSC numbers. These results uncover distinct contributions of cytokines derived from perivascular cells in separate vascular niches to HSC maintenance.

Murine Bone Marrow Niches from Hematopoietic Stem Cells to B Cells

“…When pericytes were specifically depleted upon injection of tamoxifen and diphtheria toxin in NG2-CreERT / ROSA26iDTR mice (iDTR: inducible Diphteria Toxin Receptor), HSC were decreased and less quiescent and relocalized away from arteries [62]. A similar effect was observed upon the specific deletion of CXCL12, but not of SCF, from pericytes [51]. …”

Pericytes are heterogeneous in their origin within the same tissue

“…Additionally, arteriolar pericytes express the pericytic marker NG2 proteoglycan, and do not express leptin receptor; while sinusoidal pericytes express leptin receptor, but lack NG2 expression (Kunisaki et al, 2013). Interestingly, although both pericyte subtypes produce the chemokine C-X-C motif ligand 12 (CXCL12), only Cxcl12 derived from arteriolar pericytes is importante for HSC maintenance (Asada et al, 2017). The embryonic origin and the developmental relationship of bone marrow pericyte subpopulations remain to be elucidated.…”

Pericytes constrict blood vessels after myocardial ischemia

“…Pericytes are heterogeneous regarding their distribution, phenotype, marker expression, origin, and function [16,31–47], several subtypes have been characterized in various organs [11,17–20], including the heart [21]. Cardiac pericytes subpopulations, type-1 (NG2 +/Nestin-GFP−) and type-2 (NG2 +/Nestin-GFP +) pericytes, were identified in the perivascular space of cardiac blood vessels using bitransgenic Nestin-GFP/NG2-DsRed mice [21].…”