The hematopoietic stem cell niche in homeostasis and disease

Abstract

The bone marrow microenvironment contains a heterogeneous population of stromal cells organized into niches that support hematopoietic stem cells (HSCs) and other lineage-committed hematopoietic progenitors. The stem cell niche generates signals that regulate HSC self-renewal, quiescence, and differentiation. Here, we review recent studies that highlight the heterogeneity of the stromal cells that comprise stem cell niches and the complexity of the signals that they generate. We highlight emerging data that stem cell niches in the bone marrow are not static but instead are responsive to environmental stimuli. Finally, we review recent data showing that hematopoietic niches are altered in certain hematopoietic malignancies, and we discuss how these alterations might contribute to disease pathogenesis.

Figure 1

Stem cell niches in the bone marrow. Current data support 2 niches in the bone marrow. (A) Sinusoidal-megakaryocyte niche. The sinusoidal-megakaryocyte niche contains sinusoidal endothelial cells, megakaryocytes, and CAR cells. (B) Arteriolar-pericyte niche. The arteriolar niche includes arteriolar endothelial cells, NG2⁺ arteriolar pericytes, CAR cells, sympathetic nerves, and nonmyelinating Schwann cells. (A-B) A subset of HSCs localize near the endosteum, placing osteoblast lineage cells (OB) in these niches.

Figure 2

Model of G-CSF–induced HSPC mobilization. Under basal conditions, monocytic cells in the bone marrow (here shown as macrophages) provide signals that help maintain CXCL12 expression from multiple mesenchymal stromal cell populations, including osteoblasts (Ob) and CAR cells. In response to infection, systemic levels of G-CSF are often increased. G-CSF signaling in monocytic cells leads to a loss of macrophages in the bone marrow. This, in turn, results in reduced CXCL12 expression from mesenchymal stromal cells and HSPC mobilization.

Figure 3

Malignant cells alter the HSC niche. Malignant (Malig) cells secrete factors including CCL3 and IL1β that, directly or through monocytic cells (here shown as macrophages) or sympathetic nerves, respectively, target multiple stromal cell populations implicated in the HSC niche, including CAR cells and osteoblasts (Ob). This results in decreased stromal cell CXCL12 expression and potentially other changes, which in turn, increase niche support of malignant cells over normal HSCs.