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No place like home: anatomy and function of the stem cell niche

Key Points

  • Stem cells reside within fixed anatomical compartments — called niches — which provide a specialized environment to regulate the rate of stem cell proliferation, determine the fate of stem cell daughters, and protect stem cells from exhaustion or death. Many features of stem cell niches are conserved among diverse organisms and in multiple tissues, including signals from secreted factors and support cells, cell adhesion, mechanical inputs and spatial cues.

  • The formation and activity of niches are carefully regulated to ensure appropriate stem cell function. Niches form at discrete developmental times, and their appearance often enables the establishment or recruitment of stem cells at particular anatomic locations.

  • Because stem cells may function either homeostatically (continually replacing short-lived mature cells that are lost because of normal cell turnover) or facultatively (replacing differentiated cells only in response to injury or disease), stem cell niches must be dynamic enough to provide proper developmental and physiological cues to regulate stem cell behaviour normally and to mobilize stem cell activity in response to acute pathological conditions.

  • Deficient niche function may cause the loss or deregulation of tissue stem cells. Niche dysfunction contributes to age-associated deficiencies of stem cell function and, because niche cells normally control stem cell division, loss of input from the niche may permit overproliferation of stem cells, predisposing to malignant transformation.

  • An improved understanding of the relationship between stem cells and their niches will facilitate the recreation of niches in vitro, as well as in vivo manipulation of the niche to modulate endogenous stem cell function, yielding new and improved stem-cell-based therapies.

Abstract

Stem cells are rare cells that are uniquely capable of both reproducing themselves (self-renewing) and generating the differentiated cell types that are needed to carry out specialized functions in the body. Stem cell behaviour, in particular the balance between self-renewal and differentiation, is ultimately controlled by the integration of intrinsic factors with extrinsic cues supplied by the surrounding microenvironment, known as the stem cell niche. The identification and characterization of niches within tissues has revealed an intriguing conservation of many components, although the mechanisms that regulate how niches are established, maintained and modified to support specific tissue stem cell functions are just beginning to be uncovered.

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Figure 1: Components and functions of stem cell niches.
Figure 2: Multiple roles for Wnt signalling within stem cell niches.
Figure 3: Targeting the niche for therapy.

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Acknowledgements

The authors would like to thank H. Mikkola, D. Laird, N. Geijsen and members of the Jones and Wagers laboratories for advice and comments on the manuscript. D.L.J. is supported by an Ellison Medical Foundation New Scholar Award, the American Federation for Aging Research, the G. Harold and Leila Y. Mathers Charitable Foundation, and a National Institutes of Health grant. A.J.W. is supported by a Burroughs Wellcome Fund Career Award, a Pilot Grant from the Paul F. Glenn Laboratories, and by the Harvard Stem Cell Institute. We apologize to those colleagues whose work has not been cited directly owing to space limitations.

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Glossary

Niche

An anatomical structure, including cellular and acellular components, that integrates local and systemic factors to regulate stem cell proliferation, differentiation, survival and localization.

Stromal cell

A type of cell that contributes to the structure and connective tissue aspects of an organ.

Trabecular bone

A porous, or spongy, type of bone that is filled with red bone marrow, which appears to be enriched for HSCs in adults.

Osteoblast

A cell that is responsible for bone formation and maintenance.

Seminiferous tubule

The site of spermatogenesis in the testis. The tubules are lined with spermatogonial stem cells and spermatogonia that will eventually progress through meiosis and differentiate into mature spermatozoa. Somatic Sertoli cells also line the tubules and support spermatogenesis by promoting germ cell proliferation and survival.

Transit amplifying cell

A proliferating cell, derived from tissue stem cells, that lacks long-term self-renewal activity and serves as a precursor for more differentiated cell types.

Adherens junction

A protein complex that occurs at cell–cell junctions in epithelial tissues. It is usually situated more basally than tight junctions. The primary proteins involved in forming adherens junctions are cadherins.

Cadherin

One of a family of transmembrane proteins that form homodimers in a Ca2+-dependent manner with other cadherin molecules on adjacent cells.

Neuroblast

A stem cell that is derived from the neural ectoderm (neurectoderm) and produces cells that subsequently differentiate into neurons.

Mast cells

A haematopoietic lineage cell that is rich in cytoplasmic granules that contain protein mediators, such as histamine, which are released on cell activation. Mast cells are found in many tissues and are implicated in allergy and host defence.

Niche cell

A cell that interacts with a stem cell in a defined anatomical microenvironment (niche). Niche cells can also be referred to as 'support cells' and /or 'supporting stromal cells'.

Primordial germ cell

An embryonic cell that serves as a precursor for the germline (egg and sperm).

Parabiotic

A term referring to animals that are surgically joined such that they share a common blood circulation.

Glial cell-line-derived neurotrophic factor

(GDNF). A cytokine, often primarily considered to be a neurotrophic factor, that has a role in numerous biological processes including cell survival, neurite outgrowth, cell differentiation and cell migration. GDNF is also secreted by Sertoli cells in the seminiferous tubules, and activates the maintenance of spermatogonial stem cells.

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Jones, D., Wagers, A. No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol 9, 11–21 (2008). https://doi.org/10.1038/nrm2319

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