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Intestinal stem cells count self-renewal divisions to switch multipotency
Dong Tong1, Anqi Li1, Quanquan Jiang2
1Department of Medical Genetics, School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Nature
|July 29, 2026
Summary
Multipotent stem cells count divisions epigenetically to maintain tissue homeostasis. Histone modifications track divisions, ensuring correct cell type ratios for tissue health.
Area of Science:
- Stem cell biology
- Epigenetics
- Developmental biology
Background:
- Multipotent stem cells maintain tissue homeostasis by producing specific cell types in set ratios.
- The mechanism by which stem cells coordinate cell type ratios during repeated divisions is not fully understood.
- Drosophila intestinal stem cells (ISCs) maintain a constant ratio of enteroendocrine cells (EECs) to enterocytes (ECs) despite rapid tissue turnover.
Purpose of the Study:
- To investigate how Drosophila intestinal stem cells (ISCs) intrinsically count self-renewal divisions.
- To elucidate the epigenetic mechanisms controlling multipotency switching in ISCs.
- To understand how ISCs maintain consistent ratios of enteroendocrine cells (EECs) and enterocytes (ECs).
Main Methods:
- Tracking division counts in Drosophila intestinal stem cells (ISCs).
- Analyzing histone modifications (H3K4me3, H3K36me3, H3K27me3) associated with division counting.
- Investigating the role of Trithorax group (TrxG) and Polycomb group (PcG) proteins.
- Examining the influence of Notch signaling from enteroendocrine mother cells (EMCs).
Main Results:
- ISCs intrinsically count divisions using an epigenetic mechanism involving histone modifications.
- Active histone marks (H3K4me3, H3K36me3) decrease, while repressive marks (H3K27me3) increase over divisions.
- This epigenetic counting mechanism triggers a switch in cell fate production after a specific number of divisions (nine).
- The division count is adjustable by modulating TrxG and PcG activity and is resilient to injury.
Conclusions:
- A histone-modification-based division counter programs developmental fidelity in stem cells.
- This mechanism ensures consistent cell type ratios, crucial for tissue homeostasis.
- Findings have implications for engineered tissue growth and therapies for differentiation disorders.
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