PerspectiveNeuroscience

Cellular Interactions in the Stem Cell Niche

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Science  28 May 2004:
Vol. 304, Issue 5675, pp. 1253-1255
DOI: 10.1126/science.1099344

The ability of stem cells to both self-renew and differentiate into many different cell types enables these versatile cells to generate and repair tissues and organs. Yet studies of the fruit fly Drosophila and of mammalian skin, intestine, bone marrow, and brain reveal that these inherent stem cell features are tightly regulated by the cells and proteins that constitute the extracellular environment (or “niche”) that stem cells inhabit (1). On page 1338 of this issue, Shen et al. (2) take an important step forward in our understanding of the stem cell niche. They show that endothelial cells (ECs) that are enriched in the niche occupied by neural stem cells (NSCs) regulate NSC proliferation and induce these stem cells to become neurons in vitro.

It is well established that NSCs are not randomly distributed throughout the brain, but rather are concentrated around blood vessels (see the figure) (35). This location places NSCs in close proximity to the ECs that line blood vessels, facilitating communication between these two cell types (36). To test the degree of intercellular communication between NSCs and ECs, Shen et al. cultured NSCs and monitored changes in their behavior when ECs were brought into close proximity (2). These investigators maintained cultures of mouse embryonic NSCs (derived from the cerebral cortex of 10- to 11-day-old mouse embryos) by adding fibroblast growth factor-2. Under these conditions, NSCs proliferated slowly and many of them exited the cell cycle, choosing to differentiate instead (2). However, when NSCs were cocultured with ECs their proliferation rate doubled, resulting in the formation of large interconnected sheets of undifferentiated cells. A clever aspect of Shen et al.'s strategy was to introduce ECs into NSC cultures by means of transwell inserts. The pores of the transwells were too small to allow cell-cell contact between NSCs and ECs, but were large enough to enable signaling factors secreted by ECs to diffuse into the NSC cultures. Remarkably, the removal of transwells containing ECs triggered the coordinated differentiation of proliferating NSCs into neurons. Only 9% of NSCs unexposed to ECs expressed mature neuronal markers, compared with 31 to 64% of NSCs exposed to the EC transwells. This trend also was observed with cultured NSCs derived from the subventricular zone of adult mouse brain (2). Thus, signaling molecules secreted by ECs induced a shift in the mixed population of proliferating and differentiating NSCs, pushing them toward self-renewal while simultaneously priming them for the production of neurons.

Neurogenesis in the NSC niche.

(Top) The niche inhabited by mammalian adult NSCs is situated close to blood vessels. NSCs interact with ECs that line the blood vessels and with astrocytes. (Bottom) Both ECs and astrocytes secrete signaling molecules that influence neighboring NSCs to proliferate and to differentiate into neurons.

CREDIT: KATHARINE SUTLIFF/SCIENCE

The neurogenic effects of ECs could not be mimicked by fibroblasts or by vascular smooth muscle cells (2), indicating that not all cell types alter the NSC differentiation profile. The new work expands the importance of ECs beyond their traditional role as structural components of blood vessels. ECs are known to enhance neurogenesis, possibly through the secretion of brain-derived neurotrophic factor, and to induce astrocyte differentiation within the optic nerve (5, 7). But ECs are not limited to instructing the neural lineages—they also promote formation of pancreatic and liver tissue independently of their ability to form vasculature (8, 9). Indeed, ECs may be instructive for many different cell types and tissues. It remains to be determined whether ECs in different tissues or at different developmental time periods display variations in their profiles of secreted signaling molecules. Cumulatively, these studies provide evidence that ECs are important tissue architects, specifying the fates of many different neighboring cell types including NSCs.

Elucidating the signaling molecules secreted by ECs that elicit NSC proliferation and neuron production remains an important goal. Such information would circumvent the need for NSC-EC coculture and potentially could facilitate the production of neurons for future clinical applications. Identification of such factors should help to elucidate whether ECs boost the neurogenic potential of NSCs directly or by enhancing the survival of differentiating neurons.

Most noteworthy are the potential implications of the Shen et al. work. First, if the influence of ECs on NSCs in vitro is conserved in an in vivo setting, a new therapeutic avenue for neuronal induction may be on the horizon. Moreover, NSCs in vivo are likely to be influenced by a convergence of signals from many neighboring cell types. Astrocytes, for instance, enhance the proliferative and neurogenic properties of NSCs by a factor of 2 and 6, respectively (10). Simultaneously combining the effects of ECs and astrocytes, if technically feasible, could elevate the production of neurons from NSCs beyond what is observed individually with either cell type (see the figure).

Researchers use a wide range of techniques to isolate and grow NSCs in vitro. It will be interesting to see whether the neurogenic and proliferative effects of ECs on NSCs cultured by the Shen et al. method are observed with NSCs grown in different culture systems. The Shen et al. work establishes EC-NSC coculture as an important tool for promoting NSC self-renewal and differentiation into neurons. With more extensive study, this method ultimately may prove to be useful for cell replacement therapy.

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