Single-Cell Transcript Profiles Reveal Multilineage Priming in Early Progenitors Derived from Lgr5+ Intestinal Stem Cells

Tae Hee Kim, Assieh Saadatpour, Guoji Guo, Madhurima Saxena, Alessia Cavazza, Niyati Desai, Unmesh Jadhav, Lan Jiang, Miguel N. Rivera, Stuart H. Orkin, Guo Cheng Yuan, Ramesh A. Shivdasani

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Lgr5+ intestinal stem cells (ISCs) drive epithelial self-renewal, and their immediate progeny—intestinal bipotential progenitors—produce absorptive and secretory lineages via lateral inhibition. To define features of early transit from the ISC compartment, we used a microfluidics approach to measure selected stem- and lineage-specific transcripts in single Lgr5+ cells. We identified two distinct cell populations, one that expresses known ISC markers and a second, abundant population that simultaneously expresses markers of stem and mature absorptive and secretory cells. Single-molecule mRNA in situ hybridization and immunofluorescence verified expression of lineage-restricted genes in a subset of Lgr5+ cells in vivo. Transcriptional network analysis revealed that one group of Lgr5+ cells arises from the other and displays characteristics expected of bipotential progenitors, including activation of Notch ligand and cell-cycle-inhibitor genes. These findings define the earliest steps in ISC differentiation and reveal multilineage gene priming as a fundamental property of the process.

Original languageEnglish
Pages (from-to)2053-2060
Number of pages8
JournalCell Reports
Volume16
Issue number8
DOIs
StatePublished - 23 Aug 2016
Externally publishedYes

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