Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy
Basak, Onur; Krieger, Teresa G.; Muraro, Mauro J.; Wiebrands, Kay; Stange, Daniel E.; Frias-Aldeguer, Javier; Rivron, Nicolas C.; van de Wetering, Marc; van Es, Johan H.; van Oudenaarden, Alexander; Simons, Benjamin D.; Clevers, Hans
(2018) Proceedings of the National Academy of Sciences of the United States of America, volume 115, issue 4, pp. E610 - E619
(Article)
Abstract
The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in
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a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67iresCreER allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.
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Keywords: Cellular dynamics, Ki67, Modeling, Neural stem cells, Single-cell sequencing, General
ISSN: 0027-8424
Publisher: National Academy of Sciences
Note: Funding Information: aHubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands; bCancer Genomics Netherlands, University Medical Center Utrecht, 3584 GC, Utrecht, The Netherlands; cThe Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom; dMERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229ER, Maastricht, The Netherlands; ePrincess Máxima Centre, 3584 CT, Utrecht, The Netherlands; fCavendish Laboratory, Department of Physics, University of Cambridge, Cambridge CB3 0HE, United Kingdom; and gWellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1TN, United Kingdom Funding Information: We thank Anko de Graaff for imaging support, Maaike van den Born for excellent technical assistance with mouse experiments, Harry Beugthel for help with histology, Jeroen Korving for ES cell injections, Stefan van der Elst for assistance with FACS sorting, Prof. Okano for kindly providing reagents, all members of the H.C. and B.D.S. group for useful discussions, and the Hubrecht Institute animal caretakers for animal support. This work was supported by NIRM/ Clevers and Stichting Vrienden van het Hubrecht (O.B.), EU/232814-StemCellMark and Skolkovo 077 MPA (J.H.v.E.), NIH/MIT Subaward 5710002735 (to D.E.S.), KWF/PF-HUBR 2007-3956 and Stichting Vrienden van het Hubrecht (M.v.d.W.), European Research Council Advanced Grant ERC-AdG 294325-GeneNoiseControl (to K.W. and A.v.O.), and Wellcome Trust Grant 098357/Z/12/Z (to B.D.S.). Funding Information: (M.v.d.W.), European Research Council Advanced Grant ERC-AdG 294325-GeneNoiseControl (to K.W. and A.v.O.), and Wellcome Trust Grant 098357/Z/12/Z (to B.D.S.). Funding Information: ACKNOWLEDGMENTS. We thank Anko de Graaff for imaging support, Maaike van den Born for excellent technical assistance with mouse experiments, Harry Beugthel for help with histology, Jeroen Korving for ES cell injections, Stefan van der Elst for assistance with FACS sorting, Prof. Okano for kindly providing reagents, all members of the H.C. and B.D.S. group for useful discussions, and the Hubrecht Institute animal caretakers for animal support. This work was supported by NIRM/ Clevers and
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