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Cell Stem Cell. 2016 Oct 6;19(4):530-543. doi: 10.1016/j.stem.2016.07.004. Epub 2016 Aug 11.

Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators.

Author information

1
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02445, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
2
Graduate Program in Cellular and Molecular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA; Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
3
Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
4
Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02445, USA.
5
Indiana University, Indianapolis, IN 46202, USA.
6
Imperial College London, London SW7 2AZ, UK.
7
School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
8
Walter and Eliza Hall Research Institute, Parkville, VIC 3052, Australia.
9
University of Turku, Turku 20014, Finland.
10
Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
11
Gifu University, Gifu 501-1193, Japan.
12
Graduate Program in Cellular and Molecular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA; Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA. Electronic address: guo-fu.hu@tufts.edu.
13
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02445, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: david_scadden@harvard.edu.

Abstract

Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on the differential single-cell gene expression analysis of mesenchymal osteolineage cells close to, and further removed from, hematopoietic stem/progenitor cells (HSPCs) to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. We functionally examined, among the genes that were preferentially expressed in proximal cells, three secreted or cell-surface molecules not previously connected to HSPC biology-the secreted RNase angiogenin, the cytokine IL18, and the adhesion molecule Embigin-and discovered that all of these factors are HSPC quiescence regulators. Therefore, our proximity-based differential single-cell approach reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance the understanding of microenvironmental regulation of stem cell function.

PMID:
27524439
PMCID:
PMC5402355
DOI:
10.1016/j.stem.2016.07.004
[Indexed for MEDLINE]
Free PMC Article

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