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Unbiased recording of clonal potency reveals species-specific regulation of mammalian intestine

Islam, M.; Bechard, M. E.; Yang, Y.; Simmons, A. J.; Xu, Y.; Higginbotham, J. N.; Zhao, P.; Cao, Z.; Tasneem, N.; Glass, S. E.; Markham, N. O.; Revetta, F.; Ramirez-Solano, M. A.; Liu, Q.; Franklin, J. L.; Lau, K.; Coffey, R. J.

2025-06-12 genomics
10.1101/2025.06.10.658707 bioRxiv
Show abstract

The mammalian intestine regenerates rapidly after damage, yet the clonal dynamics and species-specific regulation of different populations remain poorly understood. Here we used synthetic or naturally occurring DNA alterations to reconstruct clonal histories of the mouse and human intestinal epithelium at single-cell resolution. In mice, we uncovered the clonal architecture of different cell types and their roles in regeneration, supporting a hierarchical regenerative response model. We identified a rare embryonic precursor population that persisted in the adult and was crucial for regeneration after irradiation. This population was marked by Tob2, which is required for nuclear transport of Ascl2. A parallel clonal analysis of 65 human colonic biopsies revealed secretory lineage bias and an age-associated decline in clonal diversity in the distal colon. Unlike highly proliferative murine Lgr5+ stem cells, human LGR5+ cells were found largely quiescent, revealing species-specific difference in clonal potency, and suggesting a distinct regulation of intestinal stemness.

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