Where Hematopoietic Stem Cells Live: The Bone Marrow Niche

Abstract

Hematopoietic stem cells (HSCs) can sustain the production of blood throughout one's lifetime. However, for proper self-renewal of its own population and differentiation to blood, the HSC requires a specialized microenvironment called the "niche." Recent Advances: Recent studies using novel mouse models have shed new light on the cellular architecture and function of the HSC niche. Here, we review the different cells that constitute the HSC niche and the molecular mechanisms that underlie HSC and niche interaction. We discuss the evidence and potential features that distinguish the HSC niche from other microenvironments in the bone marrow. The relevance of the niche in malignant transformation of the HSCs and harboring cancer metastasis to the bone is also outlined. In addition, we address how the niche may regulate reactive oxygen species levels surrounding the HSCs. Critical Issues and Future Directions: We propose future directions and remaining challenges in investigating the niche of HSCs. We discuss how a better understanding of the HSC niche may help in restoring an aged hematopoietic system, fighting against malignancies, and transplanting purified HSCs safely and effectively into patients. Antioxid. Redox Signal. 00, 000-000.

Keywords: bone marrow; hematopoiesis; hematopoietic stem cell; leukemia; niche; transplantation.

FIG. 1.

The age-related changes observed among old HSCs. HSC, hematopoietic stem cell. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Expression of Hoxb5 and α-catulin genes in hematopoietic cells based on microarray transcriptome. a-catulin is enriched in HSCs; however, Hoxb5 is more specific for the HSC population. CLP, common lymphoid progenitor; CMP, common myeloid progenitor; GMP, granulocyte-monocyte progenitors; MPP, multipotent progenitors. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Cellular and molecular architecture of the HSC niche. Sinusoid niche with interacting Lepr⁺ stromal cells as well as arteriole niche with NG2⁺Nestin^high pericytes were proposed as the preferential localization of HSCs in the bone marrow. Macrophages and megakaryocytes were shown to be in proximity to HSCs in the bone marrow. Endothelial and stromal cells produce the indispensable factors for HSC maintenance: SDF-1 and SCF. Megakaryocytes are a source of CXCL4 and TGF-β. SCF, stem cell factor; TGF-β, transforming growth factor beta. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Localization of different niche populations in the bone marrow and their role in maintaining HSC function based on Scf^fl/fl and Cxcl12^fl/fl mice models. Lepr-Cre, LEPR⁺ stromal cells. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Distinct phenotype and characteristic of HSCs and downstream progenitors. IL, interleukin. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Proposed model of leukemic transformation in bone marrow niche. HSCs are predisposed to accumulate mutations. The first mutations occur often in epigenetic regulating genes. Preleukemic HSCs acquire more mutations and expand. The final transforming mutation occurs in progenitor cells derived from preleukemic HSCs and governs the self-renewal. The Notch pathway and b-catenin signaling alterations, RARγ-, Dicer-1-, and Sbds deficiency among the osteoblast lineage contribute to the leukemic transformation. RARγ, retinoic acid receptor gamma. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars