Making sense of hematopoietic stem cell niches

Abstract

The hematopoietic stem cell (HSC) niche commonly refers to the pairing of hematopoietic and mesenchymal cell populations that regulate HSC self-renewal, differentiation, and proliferation. Anatomic localization of the niche is a dynamic unit from the developmental stage that allows proliferating HSCs to expand before they reach the bone marrow where they adopt a quiescent phenotype that protects their integrity and functions. Recent studies have sought to clarify the complexity behind the HSC niche by assessing the contributions of specific cell populations to HSC maintenance. In particular, perivascular microenvironments in the bone marrow confer distinct vascular niches that regulate HSC quiescence and the supply of lineage-committed progenitors. Here, we review recent data on the cellular constituents and molecular mechanisms involved in the communication between HSCs and putative niches.

Figure 1

The adult bone marrow HSC niche. The vasculature has emerged as a key structure for the maintenance of HSCs in the bone marrow. Dormant HSCs are found around arterioles where factors such as CXCL12 and SCF secreted by perivascular, endothelial, Schwann, and sympathetic neuronal cells promote their maintenance. Less quiescent or activated HSCs are located near sinusoidal niches which are likely diverse in their influence for self-renewal, proliferation, and differentiation. Hematopoietic cells such as macrophages or megakaryocytes are examples of HSC-derived progeny that can feed back to the niche to influence HSC migration or proliferation. GFAP, glial fibrillary acidic protein; TGF-β1, transforming growth factor beta-1.

Figure 2

Hierarchy of the stromal niche cells. MSPC populations are found in both bone and bone marrow compartments and contribute to the generation of mesenchymal lineage cells that generate bone, fat, and cartilage tissues. The relationship between bone-derived MSPCs and marrow MSPCs remains unclear. Stromal cells are also thought to derive from MSPCs, but the nature or origin of most stromal cells is still obscure. Self-renewing mesenchymal cells and their progeny can be prospectively isolated by using specific surface markers and lineage tracing approaches with transgenic labeling to decipher the origin of niche cells. Arrows with solid lines indicate that one cell population that can give rise to another cell population; arrows with dashed lines indicate a relationship between cell populations that remains to be clarified. Mx-1, Myxovirus resistance-1; Prx-1, paired-related homeobox-1.

Figure 3

Progenitor niches and influence of differentiated progeny. (A) Microenvironment-promoting progenitors. Stromal cells labeled by Prx1-cre or Osx-cre and expressing CXCL12 (CAR cells) have been shown to regulate both lymphoid progenitor maturation and myeloid progenitor retention. Depletion of CXCL12 in Osx-cre–targeted stromal cells depletes B-lymphoid progenitor cells and induces the mobilization of myeloid progenitors from the bone marrow. Macrophages also constitute the central unit of the erythroblastic island allowing erythroblasts to mature and generate red blood cells (RBCs). (B) Regulation by HSC progeny. Macrophages promote HSC retention in the bone marrow by regulating CXCL12 production from Nes-GFP⁺ perivascular cells. Macrophage-mediated clearance of neutrophils inhibits the retention signals, which allows HSC mobilization. Regulatory T cells (T_reg) enable an immune privilege site, protecting HSCs against rejection following allogeneic transplantation. Megakaryocytes localize with HSCs and promote their quiescence. IL-10, interleukin-10.