ScienceWeek

DEVELOPMENTAL BIOLOGY: ON STEM CELL NICHES

The following points are made by K.A. Moore and I.R. Lemischka (Science 2006 311:1880):

1) Stem cell niches are composed of microenvironmental cells that nurture stem cells and enable them to maintain tissue homeostasis. An appropriate spatiotemporal dialog occurs between stem and niche cells in order to fulfill lifelong demands for differentiated cells. The niche concept was introduced in 1978 [1]; however, it was largely neglected until Drosophila studies provided a stimulus for its resurgence [2]. Niche cells provide a sheltering environment that sequesters stem cells from differentiation stimuli, apoptotic stimuli, and other stimuli that would challenge stem cell reserves. The niche also safeguards against excessive stem cell production that could lead to cancer. Stem cells must periodically activate to produce progenitor or transit amplifying (TA) cells that are committed to produce mature cell lineages. Thus, maintaining a balance of stem cell quiescence and activity is a hallmark of a functional niche.

2) The epithelial villus/crypt structure and its surrounding pericryptal fibroblasts and mesenchyme in the small intestine make up an anatomical unit that generates four cell lineages: absorptive enterocytes and the goblet, enteroendocrine, and Paneth cells of the secretory lineage. The crypt is a contiguous pocket of epithelial cells at the base of the villus. Intestinal stem cells (ISCs) and TA cells within the crypt regenerate the entire villus every 3 to 5 days [3]. Genetic marking shows that crypts are derived from individual or few ISCs and that each villus is the product of cells from several adjacent crypts [4]. There are four to six ISCs per crypt that are located in a ring about four cell diameters from the crypt bottom. Progeny of activated ISCs migrate upwards to become TA cells. When they reach the top of the crypt, TA cells stop proliferating, differentiate, and assume their appropriate positions within the villus structure. As such, proper cell-fate decisions are organized within the microanatomy of the crypt structure. Asymmetric cell division mediated by oriented mitotic planes, together with defined migratory activities within the overall crypt structure, could produce the correct localization of distinct differentiated cell types. Although asymmetric cell division along the vertical crypt axis is an attractive mechanism, this process has yet to be rigorously demonstrated in the ISC system.

3) DNA label-retention studies suggest that ISCs are normally quiescent relative to their surrounding cells [5]. This interpretation assumes symmetric partitioning of the label into both daughter cells after cell division. In contrast, an "immortal DNA strand" model proposes that a stem cell retains an initially labeled strand with each division. Such a mechanism would result in ISC label retention that is independent of proliferation. This issue needs to be clearly resolved and awaits the development of methods including those that allow the prospective isolation of ISCs.

4) In summary: A constellation of intrinsic and extrinsic cellular mechanisms regulates the balance of self-renewal and differentiation in all stem cells. Stem cells, their progeny, and elements of their microenvironment make up an anatomical structure that coordinates normal homeostatic production of functional mature cells.

References (abridged):

1. R. Schofield, Blood Cells 4, 7 (1978)

2. H. Lin, Nat. Rev. Genet. 3, 931 (2002)

3. C. S. Potten, M. Loeffler, Development 110, 1001 (1990)

4. J. I. Gordon, G. H. Schmidt, K. A. Roth, FASEB J. 6, 3039 (1992)

5. C. Booth, C. S. Potten, J. Clin. Invest. 105, 1493 (2000)

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