The stem cell niche: theme and variations

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Stem cells in animal tissues are often located and controlled by special tissue microenvironments known as niches. Studies of stem cell niches in model systems such as Drosophila have revealed adhesive interactions, cell cycle modifications and intercellular signals that operate to control stem cell behavior. Candidate niches and regulatory molecules have also been identified in many mammalian tissues, including bone marrow, skin, gut and brain. While niches are an ancient evolutionary device with conserved features across diverse organisms, we suggest that certain niches display important differences in their organization and function.

Introduction

The notion that tissue stem cells reside within specific anatomical locations termed ‘niches’ arose nearly four decades ago from studies of transplanted hematopoetic progenitors [1]. The likely existence of microenvironmental factors produced by niche stromal cells has long cautioned that some aspects of stem cell biology may be difficult to deduce from purified stem cells. When the first niche to be defined at the cellular and functional level was described in the Drosophila ovary [2], stem-cell-extrinsic factors were indeed found to play a paramount role. Subsequently, stromal microenvironments likely to act as niches have been associated with an increasingly wide and diverse set of stem cells (Table 1). Hematopoetic stem cells (HSCs) reside in niches located in trabecular bone where they contact osteoblasts. Stem cells maintaining the multiple cell types of the mammalian digestive tract map to precise locations within discrete substructures (e.g. gastric units or intestinal crypts). Epidermal stem cells with the potential to replenish basal keratinocytes, hair and sebaceous glands are found in the hair follicle bulge. Ongoing cell production in the adult mammalian brain depends on astrocytes that reside in special niches within the subventricular zone of the cerebellum and the subgranular zone of the hypothalamus. These findings have already expanded the focus of stem cell research and deepened our understanding of how cell production is regulated in vivo.

The structure and properties of the best-characterized niches have been reviewed recently 3., 4., 5.. Despite this, our knowledge of niches remains limited. Variations in niche anatomy and regulatory mechanisms are just beginning to emerge. Here we consider recent studies of stem cell niches and suggest that multiple subtypes of niche may exist. Discerning such differences is likely to help us better understand how these remarkably small, simple units influence tissue growth, repair and aging.

Section snippets

Simple niches

We define a stem cell niche as ‘a specific location in a tissue where stem cells can reside for an indefinite period of time and produce progeny cells while self-renewing’. Many recently characterized niches, especially those in gonadal, epithelial and digestive tissue, appear to be surprisingly simple in structure and to operate using common mechanisms (Figure 1a). Often, specific junctions anchor a small number of stem cells adjacent to particular stromal partner cells (Table 1). In several

Complex niches

Some niches appear to be more complex than the relatively simple examples described above. For example, subventricular zone (SVZ) neural stem cells closely associate with and sometimes specifically contact other astrocytes, neuroblasts, ependymal cells, endothelial cells and a factor-rich basal lamina 18., 19., 20., 21.••, 4.. The great cellular complexity of the nervous system may require that stem cell activity be subject to more controls than are required for other tissues. Indeed, the

Storage niches

A potentially different type of niche, the ‘storage niche’, may contain quiescent stem cells (Figure 1c). The bulge region of the mouse hair follicle currently represents the canonical example of such a niche. During most of the hair cycle and in the absence of wounding, transient epithelial stem cells and melanoblasts in the basal keratinocyte layer and the hair follicle matrix support ongoing skin and hair production. Reserve stem cells located in the bulge do not divide during this period

Programming daughter cells

Niches with active stem cells must contain routes for progeny cells to exit lest they burgeon into tumorous nodules. For example, HSC daughters move away from the osteoblasts of the trabecular bone and toward the center of the marrow, while spermatogonia leave the basal layer and migrate toward the lumen of the seminiferous tubule. We consider a cell to have left the niche when it reaches a location that cannot itself support a stem cell because one or more critical adhesive or signaling

Stabilizing daughter cell fates

A stem cell daughter that encounters an empty niche can sometimes enter and become a stem cell again. Most cells, by contrast, once they have begun to differentiate, appear to be precluded from reverting, at least under normal conditions. Recently, Kai and Spradling [36••] showed that interconnected germ cells in four- and eight-cell cysts can detach from their neighbors and revert to fully functional stem cells with very high efficiency when placed in the context of a larval ovary, or an adult

Summary

Niches have emerged as a major mechanism of stem cell regulation. Our knowledge of niches remains very limited, but is starting to grow and solidify. Discerning differences such as those proposed in this review may help reveal how these remarkably small, simple units influence tissue development, growth, repair and aging.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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