A breakthrough discovery by Professor Guo Zheng’s team from the School of Basic Medicine at Tongji Medical College, Huazhong University of Science and Technology (HUST), was published in Nature on July 30.

The research challenges the conventional academic belief that the differentiation ratio of stem cells is dictated by random probability, unveiling a cell division counting mechanism regulated by epigenetics. This also explains the principle by which tissues maintain stable cell proportionality.

Guo Zheng’s team selected intestinal stem cells in fruit flies (Drosophila melanogaster) as their model organism. Their observations revealed that stem cells follow a fixed differentiation cycle: they undergo eight rounds of cell division to form absorptive cells (enterocytes), then one round to form secretory cells (enteroendocrine cells).

Upon the ninth division, they switch their differentiation direction, maintaining a stable proportion of enteroendocrine cells at approximately 10% of the intestinal epithelium. This counting program continues to operate stably even under gut injury conditions.

At the molecular level, the study introduces an epigenetic counter model, dissecting the molecular regulatory pathways. After producing an enteroendocrine mother cell, the newly formed daughter cells activate Notch signaling in ISCs, by which they generate active histone markers on ISC chromatin. As ISC division progresses, the active markers gradually dilute while inhibitory markers steadily accumulate. Reaching the threshold of the ninth division, stem cells shift back to producing enteroendocrine cells.

This discovery sheds light on a fundamental universal design principle by which living organisms build and maintain robustness, offering novel technological approaches for regenerative medicine and in vitro organ cultivation, while providing potential intervention targets for diseases stemming from differentiation disorders.

The corresponding author of the paper is Professor Guo Zheng. Doctors Tong Dong and Li Anqi from the School of Basic Medicine are the co-first authors, with HUST as the first author’s affiliated institution.

Source: Public Relations Office, News Center, and School of Basic Medicine of Tongji Medical College, HUST