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

Lev Silberstein, Kevin A. Goncalves, Peter V. Kharchenko, Raphael Turcotte, Youmna Kfoury, Francois Mercier, Ninib Baryawno, Nicolas Severe, Jacqueline Bachand, Joel A. Spencer, Ani Papazian, Dongjun Lee, Brahmananda Reddy Chitteti, Edward F. Srour, Jonathan Hoggatt, Tiffany Tate, Cristina Lo Celso, Noriaki Ono, Stephen Nutt, Jyrki HeinoKalle Sipilä, Toshihiro Shioda, Masatake Osawa, Charles P. Lin, Guo fu Hu, David T. Scadden

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)530-543
Number of pages14
JournalCell Stem Cell
Volume19
Issue number4
DOIs
StatePublished - Oct 6 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Silberstein, L., Goncalves, K. A., Kharchenko, P. V., Turcotte, R., Kfoury, Y., Mercier, F., Baryawno, N., Severe, N., Bachand, J., Spencer, J. A., Papazian, A., Lee, D., Chitteti, B. R., Srour, E. F., Hoggatt, J., Tate, T., Lo Celso, C., Ono, N., Nutt, S., ... Scadden, D. T. (2016). Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators. Cell Stem Cell, 19(4), 530-543. https://doi.org/10.1016/j.stem.2016.07.004