Cell and chromatin transitions in intestinal stem cell regeneration

Area of Science:

• Cell biology
• Stem cell research
• Epigenetics

Background:

• Intestinal stem cells (ISCs) regenerate the gut lining, but how their progeny dedifferentiate and what epigenetic changes occur is unclear.
• The skin shows epigenetic memory after injury; it's unknown if intestinal stem cell regeneration involves similar memory.
• Understanding these processes is crucial for regenerative medicine and tissue repair.

Purpose of the Study:

• To investigate the cell sources, transitional states, and chromatin remodeling during intestinal stem cell (ISC) progeny dedifferentiation.
• To determine if regenerated ISCs in the intestine retain epigenetic memory, similar to skin stem cells.
• To deconstruct the forward and reverse differentiation of the intestinal secretory (Sec) lineage at single-cell resolution.

Main Methods:

• Examined gene activity and open chromatin in single Neurog3-labeled mouse intestinal crypt cells.
• Utilized selective ablation of the ISC compartment to trigger dedifferentiation.
• Analyzed transcriptional and chromatin features during cellular differentiation and dedifferentiation.

Main Results:

• Goblet, Paneth, and enteroendocrine cells originate from multilineage-primed precursors with selective cis-element access.
• ISC ablation induced rapid chromatin and transcriptional reversal in Sec cells without cell cycle re-entry.
• Dedifferentiation occurred along a continuum, lacking discrete intermediate states, and erased initial chromatin identities.

Conclusions:

• Intestinal stem cell (ISC) progeny exhibit remarkable plasticity, rapidly dedifferentiating upon ISC loss.
• Regenerated intestinal cells reverse differentiation trajectories without invoking developmental programs, erasing epigenetic memory.
• These findings reveal dynamic molecular frameworks governing self-renewing tissue assembly and regeneration.