Stem cells repurpose proliferation to contain a breach in their niche barrier
- Howard Hughes Medical Institute, The Rockefeller University, United States
- Janelia Research Campus, Howard Hughes Medical Institute, United States
Abstract
Adult stem cells are responsible for life-long tissue maintenance. They reside in and interact with specialized tissue microenvironments (niches). Using murine hair follicle as a model, we show that when junctional perturbations in the niche disrupt barrier function, adjacent stem cells dramatically change their transcriptome independent of bacterial invasion and become capable of directly signaling to and recruiting immune cells. Additionally, these stem cells elevate cell cycle transcripts which reduce their quiescence threshold, enabling them to selectively proliferate within this microenvironment of immune distress cues. However, rather than mobilizing to fuel new tissue regeneration, these ectopically proliferative stem cells remain within their niche to contain the breach. Together, our findings expose a potential communication relay system that operates from the niche to the stem cells to the immune system and back. The repurposing of proliferation by these stem cells patch the breached barrier, stoke the immune response and restore niche integrity.
Data availability
RNA-sequencing data have been deposited in GEO under accession number GSE106767
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RNA-seq analysis of hair follicle stem cell transcriptome upon loss of the transcription factor FOXC1NCBI Gene Expression Omnibus, GSE77256.
Article and author information
Author details
Funding
National Institutes of Health
- Elaine Fuchs
L'Oreal USA
- Shruti Naik
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were maintained in a facility approved by The Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), and procedures were performed with protocols approved by Rockefeller University's institutional animal care and use committee (IACUC) members.
Reviewing Editor
- Valerie Horsley, Yale University, United States
Publication history
- Received: September 2, 2018
- Accepted: November 29, 2018
- Accepted Manuscript published: December 6, 2018 (version 1)
- Version of Record published: January 8, 2019 (version 2)
Copyright
© 2018, Lay et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Stem cells repurpose proliferation to contain a breach in their niche barrier
eLife 7:e41661.
https://doi.org/10.7554/eLife.41661
Further reading
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- Stem Cells and Regenerative Medicine
During severe or chronic hepatic injury, biliary epithelial cells (BECs) undergo rapid activation into proliferating progenitors, a crucial step required to establish a regenerative process known as ductular reaction (DR). While DR is a hallmark of chronic liver diseases, including advanced stages of non-alcoholic fatty liver disease (NAFLD), the early events underlying BEC activation are largely unknown. Here, we demonstrate that BECs readily accumulate lipids during high-fat diet feeding in mice and upon fatty acid treatment in BEC-derived organoids. Lipid overload induces metabolic rewiring to support the conversion of adult cholangiocytes into reactive BECs. Mechanistically, we found that lipid overload activates the E2F transcription factors in BECs, which drive cell cycle progression while promoting glycolytic metabolism. These findings demonstrate that fat overload is sufficient to reprogram BECs into progenitor cells in the early stages of NAFLD and provide new insights into the mechanistic basis of this process, revealing unexpected connections between lipid metabolism, stemness, and regeneration.
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- Stem Cells and Regenerative Medicine
Stem cell differentiation requires dramatic changes in gene expression and global remodeling of chromatin architecture. How and when chromatin remodels relative to the transcriptional, behavioral, and morphological changes during differentiation remain unclear, particularly in an intact tissue context. Here, we develop a quantitative pipeline which leverages fluorescently-tagged histones and longitudinal imaging to track large-scale chromatin compaction changes within individual cells in a live mouse. Applying this pipeline to epidermal stem cells, we reveal that cell-to-cell chromatin compaction heterogeneity within the stem cell compartment emerges independent of cell cycle status, and instead is reflective of differentiation status. Chromatin compaction state gradually transitions over days as differentiating cells exit the stem cell compartment. Moreover, establishing live imaging of Keratin-10 (K10) nascent RNA, which marks the onset of stem cell differentiation, we find that Keratin-10 transcription is highly dynamic and largely precedes the global chromatin compaction changes associated with differentiation. Together, these analyses reveal that stem cell differentiation involves dynamic transcriptional states and gradual chromatin rearrangement.
