Niches for Hematopoietic Stem Cells and Their Progeny

Abstract

Steady-state hematopoietic stem cells' (HSCs) self-renewal and differentiation toward their mature progeny in the adult bone marrow is tightly regulated by cues from the microenvironment. Recent insights into the cellular and molecular constituents have uncovered a high level of complexity. Here, we review emerging evidence showing how HSCs and their progeny are regulated by an interdependent network of mesenchymal stromal cells, nerve fibers, the vasculature, and also other hematopoietic cells. Understanding the interaction mechanisms in these intricate niches will provide great opportunities for HSC-related therapies and immune modulation.

Keywords: bone marrow niche; hematopoietic stem cells; microenvironment; progenitors.

Figure 1. Interdependent cellular and molecular constituents of the BM HSC niche

Multiple cell types have been implicated to be important in the BM HSC niche via direct or indirect mechanisms. Nes-GFP⁺/CXCL12-abundant reticular (CAR)/LEPR⁺ mesenchymal stem/progenitor cells are the main contributor of niche factors, such as CXCL12 and SCF. Osteolineage cells (e.g. osteoblasts and osteocytes) have been implicated in HSPC regulation but the specific molecular signals have not been clearly elucidated. Adipocytes may be a negative regulator of the BM niche although the target of this regulation has not been determined. Endothelial cell derived signals have been shown to regulate HSC maintenance and the activity of perivascular cells. Adrenergic nerves from the sympathetic nervous system regulate HSC mobilization and hematopoietic recovery via its niche. Adrenergic nerve-associated Schwann cells may contribute to HSC quiescence through TGFβ signaling. The HSC progeny (e.g. macrophages) can indirectly regulate HSC retention via niche cells, and may also directly contribute to HSC maintenance. Other HSC progeny (megakaryocytes) can exert a feedback loop to promote HSC quiescence via direct mechanisms (CXCL4 and TGFβ) independent of the stromal niche cells. T cells may also influence HSCs directly or via the stromal cells. Neutrophils mostly contribute to HSC regulation directly or via their influence on macrophages and stromal cells. NG2, neuron-glial antigen 2, also known as chondroitin sulfate proteoglycan 4 (CSPG4); Myh11, myosin heavy chain 11; CXCL12, CXC chemokine ligand 12, also known as stromal cell-derived factor (SDF1); SCF, stem cell factor, also known as Kit ligand (KITL); CXCL4, CXC chemokine ligand 4, also known as Platelet factor 4 (PF4); TPO, Thrombopoietin; PGE2, prostaglandin E2; DARC, Duffy antigen receptor for chemokines/CD234; OSM, Oncostatin M; DPP4, Dipeptidyl peptidase-4.

Figure 2. Potential BM niche constituents of the hematopoietic progenitors

Imaging studies have suggested that MPPs likely reside further away from the endosteum than HSCs, closer to IL-7⁺ stromal cells, and also require CXCL12 for their maintenance and differentiation. It is not clear at present whether the stromal cells providing CXCL12 to progenitors are different from those thought to form the HSC niche. Several niche cells and factors have been reported to regulate lymphoid progenitors, mainly IL7 or CXCL12-producing and osteolineage cells but may also include adipocytes, regulatory T cells (Treg), monocytic cells and nerves. Myeloid progenitors (GMP) also receive cues for proliferation and differentiation from the same HSC niche cells, including CXCL12-producing stromal cells, the vasculature, and megakaryocytes. The actual spatial relationships among HSCs and their progeny in the BM are still not clear.