Journal
CELL REPORTS
Volume 16, Issue 8, Pages 2053-2060Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.07.056
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Funding
- American-Italian Cancer Foundation fellowship
- Harvard Stem Cell Institute
- Affymetrix
- Lind family
- [R01DK081113]
- [U01DK103152]
- [K99DK095983]
- [F32DK103453]
- [P50CA127003]
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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 stemand 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.
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