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  • Review Article
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Uncertainty in the niches that maintain haematopoietic stem cells

Key Points

  • Haematopoietic stem cells (HSCs) first arise in close association with intraembryonic and extraembryonic blood vessels, then undergo haematopoiesis in the fetal liver and spleen and later in the bone marrow. The bone marrow is the major site of adult haematopoiesis, but HSCs can also undergo haematopoiesis in the spleen and liver during periods of haematopoietic stress.

  • HSCs niches are specialized microenvironments that contain and sustain stem cells. The niche includes supporting cells as well as extracellular matrix and soluble factors that are found within the microenvironment. The signals in this microenvironment promote stem-cell survival and self-renewal, but may also regulate migration and differentiation to the extent that these functions must be regulated to ensure maintenance.

  • In the bone marrow, some HSCs localize at or near the endosteum (the interface of bone and bone marrow), whereas other HSCs localize around sinusoidal blood vessels, and in other locations. It is not clear whether there are multiple niches in these locations, or whether HSCs only transiently migrate through some of these locations.

  • Osteoblasts and osteoclasts at the endosteum have been proposed to form a niche for HSCs in the bone marrow, though it remains uncertain whether this niche is at the endosteal surface or whether these cells secrete factors that influence niches located close to, but not at, the endosteal surface.

  • As HSCs expand during fetal development, and engage in adult extramedullary haematopoiesis in tissues such as the liver and spleen that contain no bone or endosteum, endosteal cells cannot be the only cell types capable of creating HSC niches.

  • The presence of HSCs around sinusoids in bone marrow and extramedullary tissues raises the possibility that at least some HSCs reside in perivascular niches. Some perivascular cells also appear to secrete factors implicated in HSC maintenance, though additional work will be required to determine whether this constitutes a bona fide niche.

  • One possibility is that endosteal cells and perivascular cells work together to create a common niche near the endosteum in the trabecular zone of bone. It is also possible that there are multiple different niches in haematopoietic tissues that perform redundant or distinct roles in the maintenance of HSCs and the regulation of haematopoiesis.

  • Many of the mechanisms by which proposed niches have been suggested to promote HSC maintenance would benefit from additional studies to determine whether such mechanisms are required for HSC maintenance in vivo or to confirm through conditional deletion which cells are most responsible for the expression of key factors.

Abstract

Haematopoietic stem cell (HSC) niches are specialized microenvironments that contain stem cells and regulate their maintenance. Cells at the interface of bone and the bone marrow (the endosteum) contribute to the creation of HSC niches. It remains uncertain whether this interface itself is a niche, or whether endosteal cells secrete factors that diffuse to nearby niches. Vascular and/or perivascular cells may also create niches as many HSCs are observed around sinusoidal blood vessels, and perivascular cells secrete factors that regulate HSC maintenance. Do endosteal and perivascular cells create distinct niches, or do they contribute to a common niche? We discuss a range of niche models consistent with recent evidence.

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Figure 1: Anatomy of the adult haematopoietic organs, bone marrow and spleen.
Figure 2: Possible mechanisms by which endosteal cells contribute to the formation of HSC niches.
Figure 3: Many different cell types may contribute to formation of HSC niches near the endosteum and around sinusoids.
Figure 4: Possible reasons for the observation of HSCs in perivascular sites.
Figure 5: Possible relationships between endosteal and perivascular niches.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute. M.J.K. was supported by a fellowship from the University of Michigan Cancer Biology Training Grant. Thanks to Y. Yamashita, and L. Ding for discussing results or for commenting on the manuscript. Thanks to L. McCauley for contributing the photo shown in BOX 1, panel A.

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Glossary

HSC niche

A specialized microenvironment that contains stem cells, supports their maintenance, and regulates their function.

Endosteum

The highly vascularized interface between the bone and the bone marrow. Osteoclasts and bone-lining cells that can differentiate into osteoblasts line this surface to regulate bone remodelling and haematopoiesis.

Sinusoid

Specialized blood vessels in haematopoietic tissues through which venous circulation occurs and that have thin walls formed by a discontinuous, irregularly-shaped endothelium that allows cells to pass in and out of circulation.

Osteoblast

A mesenchymally-derived bone-forming cell that differentiates from the pre-osteoblasts that line the surface of bone.

Osteoclast

A haematopoietic cell derived from a myeloid progenitor that localizes to the bone surface and participates in bone remodelling by resorbing bone.

Trabecular bone

Tiny projections of bone found throughout the trabecular zone of bones that form a porous bone matrix in which haematopoiesis occurs and where haematopoietic stem cells often reside.

Stromal cells

Non-haematopoietic cells present in haematopoietic tissue that are thought to secrete growth factors that regulate haematopoiesis and potentially haematopoietic-stem-cell function.

Col1a1-TK transgenic mice

Mice that are transgenic for thymidine kinase, expressed under the control of the collagen 1A1 promoter, which is active in osteoblasts. When ganciclovir is administered to these mice, osteoblasts selectively undergo apoptosis making it possible to test the role of osteoblasts in haematopoiesis.

Extramedullary haematopoiesis

Haematopoiesis that occurs predominantly in the spleen and liver under conditions of stress in which the bone marrow cannot produce sufficient haematopoietic cells. Extramedullary haematopoiesis is marked by the mobilization and dramatic expansion of HSCs, other haematopoietic progenitors, and haematopoiesis in the spleen and liver.

SLAM family markers

Signalling lymphocyte activation molecule (SLAM)-family receptors, including CD150, CD244 and CD48, are differentially expressed among stem and progenitor cells at different stages of haematopoiesis, and can be used to highly purify HSCs and to localize HSCs in sections through haematopoietic tissues.

Hoechst dye

A UV-excitable DNA-binding dye that can label live cells. It has been injected intravenously to infer blood perfusion patterns in tissues. It has also been used to measure HSC DNA content (and therefore cell cycle status) and to isolate HSCs based on their propensity to efflux this dye to a greater extent than other cells.

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Kiel, M., Morrison, S. Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 8, 290–301 (2008). https://doi.org/10.1038/nri2279

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