Exciting news on neural stem cell niches: stunning research from Fiona Doetsch’s lab

http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)30163-1

Sense & Sensibility: niche signals regulate neural stem cells in an age-dependent manner

paper feature by Thomas Schwarz-Romond

Tissue specific stem cell niches provide lifelong support for adult stem cells. The cell-biological dissection of (adult neural) stem cell – niche interactions uncovered unexpected regulatory functions. These new results imply that stem cell niches actively sense (age-dependent) physiological changes and translate them into molecular cues to instruct stem cell activity.

The physiological control of stem cell activity is an intensely studied subject. Stem cells reside in so called niches, specialized compartments to nurture and protect the remarkable cellular properties of tissue-resident, totipotent cells. From a morphological perspective, the form and composition of tissue specific stem cell niches varies tremendously, being neatly adapted to accommodate the functional requirements in any given tissue. Clonal lineage-tracing strategies and conditional deletion experiments from many labs have accelerated our insights into stem cell hierarchies, best illustrated in the hematopoietic system and a growing list of epithelia stem cell compartments such as the skin, the mammary gland, the intestine or prostate1,2. At the same time, we are just beginning to capture the structural, cellular and micro-environmental components constituting tissue-specific stem cell niches3,4.

Another exciting stream of research suggests that stem cells in their respective niches are able to respond dynamically to changes in their physiological environment. In fact, GDF11 was characterized as a systemic factor to modulate muscle and neuronal stem cell function in an age- dependent manner. The same authors also revealed that GDF11 elicited some of these effects by functionally improving the vascular neurogenic niche5,6. Such data hint to contributions of stem cell niches beyond sole structural support and motivate ongoing research (i) addressing the complex cellular composition of tissue-specific stem cell niches, (ii) investigating active roles in sensing the physiological environment, and (iii) inquiries into niche components able to transform systemic signals into molecular cues to regulate niche-resident stem cells.

Along such conceptual preposition, Fiona Doetsch and her team7 explore the lateral ventricle choroid plexus (LVCP) as a putative novel component of the neural ventricular stem cell niche. A simple system to harvest conditioned medium from LVCP explants enables the authors to dissect the specific, cell-biological effects of the LVCP-secretome on neural stem cells as well as their progeny. Transcript- and proteomic evaluation of the LVCP and its secretome determines a rich

reservoir of factors known to promote neural stem cell (NSC)-quiescence, stem cell activation and proliferation, respectively. This includes chemokines, lymphokines, growth factors, hormones, ECM-components and their remodelers. Some of these (e.g. IL1B, NT3 and IGF2) had been implicated in the regulation of sub-ventricular zone (V-SVZ) stem cells before, functionally establishing the LVCP as new, and so far neglected part of the V-SVZ adult stem cell niche. Reaching further, the studies performed by Silva-Vargas et al. surface new regulators of V-SVZ stem cell activity, namely BMP5 and IGF1. Addressing the physiological significance of BMP5 and IGF1 in the control of neural stem cell activity, reveals their enrichment in young, compared to aged LVCP-secretomes, a crucial hint to age-associated fluctuations. Backed by these findings, the authors nominate the LVCP as new component of the V-SVZ neural stem cell niche. They conclude from the age-dependent changes in secretome composition that the LVCP acts as a sensor of physiological change, in turn adopting the composition of the secreted ‘cocktail’ as to accommodate environmental conditions. By extension, the results imply that niche-components in general could monitor systemic change and instruct stem cell activity in a context-dependent manner.

How do these ideas integrate with previous knowledge? It could easily be argued that the LVCP, as part of the choroid plexus, would morphological be in a prime spot to control NSC-behavior8. It was also described that the choroid plexus, a vascularized epithelium within the brain ventricle, produces the majority of the cerebrospinal fluid (CSF) and constitutes the blood-CSF barrier9. The fluid CSF-compartment had been reported to produce migratory cues for emerging neurons and factors maintaining stem cell quiescence10, while the choroid plexus itself was shown to dynamically respond to physiological inputs11. Finally, NSCs adjacent to the lateral ventricles extend projections into the CSF on one hand, and physically connect to blood vessels on the other12. Those data already provided a general scheme for the make-up of the tentative V-SVZ niche: highly connected NSCs, positioned in close proximity to the choroid plexus – the blood- cerebrospinal barrier, and hence at the interface to systemic circulation. Though seemingly distinct in morphology, such a conceptual composition appears reminiscent of the features previously described for the perivascular niche in the hematopoietic system3. Therefore, the new findings from Silva-Vargas et al.7 advance current views on the V-SVZ NSC-niche and help to generalize our understanding of stem cell-niche interactions.

Specifically, the far-reaching proposal of a niche-encoded ‘sensory- and molecular instructor’ function to control (neural) stem cell behavior significantly advances newly emerging concepts in contemporary stem cell biology and inspire eminent questions: could BMP5 and IGF1, characterized here as V-SVZ niche signals, have much broader functions? Do they operate in other stem cell niches, or even systemically, like GD11? Appreciating that specific stem cell niches employ various sets of instructive signals, new cell-biology might soon be disclosed, as so often when venturing into unknown territories13. For illustration, Wnt3, produced by (niche) paneth cells and acting in a gradient to control stemness, has recently be reported to spread in a membrane- bound fashion, instead of traveling by simple diffusion14. Further, similar-focused investigations assessing the inventory of niche components might accelerate new therapeutic interventions. This route has been elegantly exemplified in a study on muscle stem cells, with an artificially designed stem cell niche extending the quiescence of (cultured) stem cells and improving stem cell engraftment after transplantation15. In sum, continued efforts, which capitalize on the conceptual similarity and appreciate tissue specific differences in the cell-biological and molecular make up of stem cells niches will not only add exciting new chapters to basic biology textbooks but also generate tangible knowledge to inspire future therapies.