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  1. eLife assessment

    This paper is a fundamental work in developmental biology that supports its findings with compelling evidence drawn from both theoretical and experiment insights. This work will be of interest to researchers in the fields of developmental and stem cell biology as it provides a potentially general mechanism for the control of a proliferative cell population.

  2. Reviewer #1 (Public Review):

    In this manuscript, the authors use time-lapse microscopy in growing intestinal organdies and computational modelling to demonstrate a paradigm for the control of a pool of proliferative cells. They find strong correlations in the proliferative behaviour of sister cells. They propose a compartmentalised model, where cells in one compartment all have a high propensity to produce two proliferating daughter cells while cells in the other department produce daughter cells who both cease to proliferate.

    The work establishes a previously suggested paradigm for the control of fluctuations in a pool of proliferating cells. This paradigm might be relevant for tissues other than the intestine such that this work will be of relevance to the general field of stem cell biology. I found this work to be a nice combination of modelling and the conclusions overall convincing. The authors could improve upon the precision in their wording and the discussion of the scope of their modelling results.

  3. Reviewer #2 (Public Review):

    This work is an attractive mix of high-quality cellular tracking in intestinal organoids - backed by intravital live imaging of in vivo mouse intestinal crypts - with computational modelling, aimed at understanding the dynamics of fate choices of intestinal stem cells. I found the work overall convincing, with minimal theoretical simulations matching well the key novel experimental findings (strong fate symmetry across several generations).

  4. Reviewer #3 (Public Review):

    The manuscript by Huelsz-Prince et al. studies the fate of intestinal crypt cells in organoids and, to some extent, in vivo, through a combination of live cell tracking (in organoids), static in vivo lineage tracing, and mathematical modelling. They find through live imaging that the vast majority of divisions in the crypt are symmetric with respect to the proliferative potential of daughter cells (something that has previously been shown indirectly). Furthermore, they show that fate outcomes depend on the distance of the mother cell from Paneth cells, but not on the position of daughter cells relative to the latter, and the fluctuations of numbers of proliferating cells are much less than would be expected from a naive cell fate model. They suggest a two-compartment model where one compartment represents the niche with a high propensity for divisions with two proliferating daughter cells and another compartment with a high propensity of divisions with two non-proliferating daughter cells, which is consistent with the data and the observed small fluctuations.

    The work is very interesting and solid and establishes its main claims through a variety of measurements supported by mathematical modelling. The methodology is strong, using cutting-edge imaging, statistical and image analysis, and mathematical modelling. The methods firmly establish that cell divisions in the crypt are predominantly symmetric and that the propensity towards proliferating divisions increases with the proximity of the mother cell (but not of the daughter cells) to Paneth cells, a mechanism that maintains homeostatic control. Their theoretical finding that such a mechanism minimises fluctuations in cell numbers is nice but has already been reported in the authors' previous work (Kok et al. bioRxiv 2022). My only concern is that while their two-compartment model is consistent with the data, other models cannot be excluded. Most models with symmetric divisions and contact inhibition, or niche crowding control (negative feedback), where cells are expelled from a crowded niche via a differentiation rate that increases with cell numbers, would lead to similar results. The presented model can rightly be seen as a simplified paradigmatic representative of such model types, and it is a valid approach to use a simplified model to demonstrate qualitative features of this mechanism but to describe the real mechanism one should not take the two-compartment aspect too literally. Instead, the direct measurements presented in this work, showing that the propensity towards divisions with non-proliferating daughters increases with the distance of mother cells from Paneth cells, show that a model where the proliferative potential decreases continuously rather than abruptly is probably better suited to describe that mechanism.

    Apart from that, the findings are very solid and certainly of high interest to any developmental biologist working on adult stem cell fate. While here the authors only establish this mechanism for intestinal cells, it can be reasonably suggested that a similar mechanism of homeostatic control is also present in other tissues, as the prevalence of symmetric divisions has been shown for many mammalian tissues.