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 specialized 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 localization 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.

Tissue growth and function depend on vascularization, and vascular insufficiency or excess exacerbates many human diseases. Identification of the biological processes involved in angiogenesis will dictate strategies to modulate reduced or excessive vessel formation. We examine the essential role of pericytes. Their heterogeneous morphology, distribution, origins, and physiology have been described. Using double-transgenic Nestin-GFP/NG2-DsRed mice, we identified two pericyte subsets. We found that Nestin-GFP⁻/NG2-DsRed⁺ (type-1) and Nestin-GFP⁺/NG2-DsRed⁺ (type-2) pericytes attach to the walls of small and large blood vessels in vivo; in vitro, type-2, but not type-1, pericytes spark endothelial cells to form new vessels. Matrigel assay showed that only type-2 pericytes participate in normal angiogenesis. Moreover, when cancer cells were transplanted into Nestin-GFP/NG2-DsRed mice, type-1 pericytes did not penetrate the tumor, while type-2 pericytes were recruited during its angiogenesis. As inhibition of angiogenesis is a promising strategy in cancer therapy, type-2 pericytes may provide a cellular target susceptible to signaling and pharmacological manipulation in treating malignancy. This work also reports the potential of type-2 pericytes to improve blood perfusion in ischemic hindlimbs, indicating their potential for treating ischemic illnesses.

Stem cells ensure tissue regeneration, while overgrowth of adipogenic cells may compromise organ recovery and impair function. In myopathies and muscle atrophy associated with aging, fat accumulation increases dysfunction, and after chronic injury, the process of fatty degeneration, in which muscle is replaced by white adipocytes, further compromises tissue function and environment. Some studies suggest that pericytes may contribute to muscle regeneration as well as fat formation. This work reports the presence of two pericyte subpopulations in the skeletal muscle and characterizes their specific roles. Skeletal muscle from Nestin-GFP/NG2-DsRed mice show two types of pericytes, Nestin-GFP-/NG2-DsRed+ (type-1) and Nestin-GFP+/NG2-DsRed+ (type-2), in close proximity to endothelial cells. We also found that both Nestin-GFP-/NG2-DsRed+ and Nestin-GFP+/NG2-DsRed+ cells colocalize with staining of two pericyte markers, PDGFRβ and CD146, but only type-1 pericyte express the adipogenic progenitor marker PDGFRα. Type-2 pericytes participate in muscle regeneration, while type-1 contribute to fat accumulation. Transplantation studies indicate that type-1 pericytes do not form muscle in vivo, but contribute to fat deposition in the skeletal muscle, while type-2 pericytes contribute only to the new muscle formation after injury, but not to the fat accumulation. Our results suggest that type-1 and type-2 pericytes contribute to successful muscle regeneration which results from a balance of myogenic and nonmyogenic cells activation.

Introduction: Fibrosis, or scar formation, is a pathological condition characterized by excessive production and accumulation of collagen, loss of tissue architecture, and organ failure in response to uncontrolled wound healing. Several cellular populations have been implicated, including bone marrow-derived circulating fibrocytes, endothelial cells, resident fibroblasts, epithelial cells, and recently, perivascular cells called pericytes. We previously demonstrated pericyte functional heterogeneity in skeletal muscle. Whether pericyte subtypes are present in other tissues and whether a specific pericyte subset contributes to organ fibrosis are unknown. Methods: Here, we report the presence of two pericyte subtypes, type-1 (Nestin-GFP-/NG2-DsRed+) and type-2 (Nestin-GFP+/NG2-DsRed+), surrounding blood vessels in lungs, kidneys, heart, spinal cord, and brain. Using Nestin-GFP/NG2-DsRed transgenic mice, we induced pulmonary, renal, cardiac, spinal cord, and cortical injuries to investigate the contributions of pericyte subtypes to fibrous tissue formation in vivo. Results: A fraction of the lung’s collagen-producing cells corresponds to type-1 pericytes and kidney and heart pericytes do not produce collagen in pathological fibrosis. Note that type-1, but not type-2, pericytes increase and accumulate near the fibrotic tissue in all organs analyzed. Surprisingly, after CNS injury, type-1 pericytes differ from scar-forming PDGFRβ + cells. Conclusions: Pericyte subpopulations respond differentially to tissue injury, and the production of collagen by type-1 pericytes is organ-dependent. Characterization of the mechanisms underlying scar formation generates cellular targets for future anti-fibrotic therapeutics.

How HSCs populate the fetal liver: Hematopoietic stem cells (HSCs) undergo dramatic expansion in the fetal liver before migrating to their definitive site in the bone marrow. Khan et al. identify portal vessel–associated Nestin ⁺ NG2 ⁺ pericytes as critical HSC niche components (see the Perspective by Cabezas-Wallscheid and Trumpp). The portal vessel niche and HSCs expand according to fractal geometries, suggesting that niche cells—rather than factors expressed by the niche—drive HSC proliferation. After birth, arterial portal vessels transform into portal veins, and lose Nestin ⁺ NG2 ⁺ pericytes. When this happens, the niche is lost and HSCs migrate away from the neonatal liver. Science , this issue p. 176 ; see also p. 126