Mother cells control daughter cell proliferation in intestinal organoids to minimize proliferation fluctuations

Abstract

During renewal of the intestine, cells are continuously generated by proliferation. Proliferation and differentiation must be tightly balanced, as any bias toward proliferation results in uncontrolled exponential growth. Yet, the inherently stochastic nature of cells raises the question how such fluctuations are limited. We used time-lapse microscopy to track all cells in crypts of growing mouse intestinal organoids for multiple generations, allowing full reconstruction of the underlying lineage dynamics in space and time. Proliferative behavior was highly symmetric between sister cells, with both sisters either jointly ceasing or continuing proliferation. Simulations revealed that such symmetric proliferative behavior minimizes cell number fluctuations, explaining our observation that proliferating cell number remained constant even as crypts increased in size considerably. Proliferative symmetry did not reflect positional symmetry but rather lineage control through the mother cell. Our results indicate a concrete mechanism to balance proliferation and differentiation with minimal fluctuations that may be broadly relevant for other tissues.

Temporal recording of mammalian development and precancer

“…We revealed that mutational density increases at a faster rate in intestinal organoid cultures than the in vivo intestinal epithelium (Extended Data Fig. 2f), confirming that epithelial cells in organoid conditions are more proliferative [40]. Cellular turnover rates of common intestinal cell types, as inferred by mutational density, were also consistent with current knowledge (Extended Data Fig.…”

FUT2-dependent fucosylation of HYOU1 protects intestinal stem cells against inflammatory injury by regulating unfolded protein response

“…To maintain homeostasis, the balance between ISC self-renewal and differentiation must be tightly balanced [ 42 ]. In the face of various microenvironments, different stem cell fate specifications, including self-renewal and differentiation, will be initiated and adapted to the actual cellular demand.…”

“…In the face of various microenvironments, different stem cell fate specifications, including self-renewal and differentiation, will be initiated and adapted to the actual cellular demand. ISCs remodel intestinal composition in response to epithelial defects by dividing symmetrically, either forming two daughter stem cells or two daughter non-stem progenitor cells which differentiate into the diverse types of epithelial cells [ 34 , 42 ]. A recent study has also revealed that ISC proliferation and differentiation are coordinately regulated to maintain homeostasis by regulating distinct pathways [ 43 ], which keeps in line with our results that FUT2-dependent fucosylation motivates the regenerative capacity of ISCs upon inflammatory injury.…”

Slowed Intestinal Transit Induced by Less Mucus in Intestinal Goblet Cell Piezo1-Deficient Mice through Impaired Epithelial Homeostasis

“…Considering that GCs in crypts are in an environment with rich mechanical signaling changes, we speculate that decreased GC sensitivity to mechanical forces in Piezo1 ΔGC mice led to blocked epithelial renewal and homeostatic imbalance. ISC function affects intestinal development, as has been observed in colitis mice with impaired ISCs and a shorter colon [ 32 ]. Thus, the decreased CSC renewal may be responsible for the shorter colons in the Piezo1 ΔGC mice.…”