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Adhesion and polarity-driven morphogenesis: Mechanisms and constraints in tissue formation

PLOS Computational Biology

Dear Dr. Furusawa,

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Attila Csikász-Nagy

Academic Editor

PLOS Computational Biology

Stacey Finley

Section Editor

PLOS Computational Biology

Additional Editor Comments:

The reviewers raise significant points that the authors should address, including details regarding the approach and placing this work in context and addressing relevant related work.

Journal Requirements:

1) Please ensure that the CRediT author contributions listed for every co-author are completed accurately and in full.

At this stage, the following Authors/Authors require contributions: Yoshiyuki T Nakamura, Chikara Furusawa, and Kunihiko Kaneko. Please ensure that the full contributions of each author are acknowledged in the "Add/Edit/Remove Authors" section of our submission form.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The manuscript titled "Adhesion and polarity-driven morphogenesis: Mechanisms and constraints in tissue formation" by Nakamura and coworkers is a timely and elegant manuscript exploring the morphogenesis of diverse forms through cellular properties: polarity and adhesion. The manuscript is very well written and lucid and I have a few minor comments:

1: what is T is equation 1?

2: why does equation 3 have a +1 term?

3: "On the other hand, the polarity θi is controlled not only by the potential Vi but also by adhesion." Can the authors give a rationale for this?

4: "Several experimental results support the fact that apico-basal polarity is controlled by mechanical stress and is often oriented perpendicular to the adhesion surface [18, 19]." This is true of simple epithelia but not of stratified or multilaminar epithelia: do the authors implement any adhesion between cell sheets in multilaminar structures.

5: In the manuscript the authors attribute the ability to give rise to morphogenetic diversity through: two microscopic parameters: the magnitude of polarity p and the time scale of angle change τB.

do these two terms, especially the second one have biological equivalents? How would it be possible to test the predictions of the model empirically. This should be alluded to in the discussion section.

6: I may have missed it but the coauthors may not have worked with the possibility that tiny variations (or errors) in adhesion strength or polarity strength or its regulation timing. It is unlikely each cell should have equal magnitudes of these metrics. Would the morphogenesis be robust to small sets of values of such metrics rather than single values per simulation? If not addressed, this could be discussed by the authors.

Reviewer #2: The idea that cell adhesion and cell polarity, acting together, can give rise to cavities within tissues – a feature of animal embryogenesis, and in vitro models – is not a new one. If cells are sticky over their surfaces except for one region (by apicobasal polarization) and the cells readjust to minimize free energy, the equilibrium configuration would cause the non-adhesive domains to surround an interior space. This idea, perhaps first stated in (1), does not require a detailed model to be persuasive in its simplest form, and has been part of discussions about the evolution of animal body plans for several decades. (This could be made clearer in the introduction.)

The problem with the simple, intuitive idea, however, is that it represents an all-or-none model (regarding both adhesion and polarity) and is based on an equilibrium argument. Biological phenomena are rarely so binary, and these assumptions may break down. This is why mathematical and computational models like that presented here are essential to a comprehensive understanding of epithelial morphogenesis in the development of natural embryos, in comparative evolutionary biology, and in in vitro organoids. The phase diagrams provided are particularly helpful.

The following are considerations that I believe need to be addressed or better clarified to make this paper fully suitable for publication in PLOS Computational Biology:

1) Several places in the text the authors refer to both adhesive strength and “polarity strength,” as well as temporal regulation of polarity. They characterize their results, however, as being controlled by just the two polarity parameters. From the context, polarity strength is polarity-dependent adhesion, but this usage is not typical for biologists, who would find both this and “polarity strength” confusing. A key result of this paper is the effect of the ratio between the adhesive and less adhesive portions of the individual cells (i.e., in contrast to the all-or-none model). The idea of adhesive differential or ratio should be included to help visualize why or why not an interior space will form.

2) It seems that the described model is a quasi-equilibrium one, in that energy-minimizing interactions among cells lead to alignment of polarities, and this produces different morphologies, depending on values of the two control parameters. The addition of new cell by growth does not affect these assumptions. However, a 2013 paper (2), not cited here, argues that depending or the ratio of cell division rate to the parameters of Potts-based model for lumen formation, effects of nonequilibrium dynamics such as multilumens, appear. The present model would benefit from engaging with the results of Cerruti et al., possibly by introducing variation in proliferation rate.

3) Based on the model’s assumptions there should be not only predictions of possible morphologies (as provided) but also prohibited states. If any of these can be specified, they would be of interest to experimental developmental biologists (particularly if the prohibitions could be relieved by genetic manipulations), and evolutionary biologists.

(1) Newman, S.A., 1998. Epithelial morphogenesis: a physico-evolutionary interpretation, in: Chuong, C.-M. (Ed.), Molecular Basis of Epithelial Appendage Morphogenesis. R. G. Landes, Austin, TX, pp. 341-358.

(2) Cerruti, B., Puliafito, A., Shewan, A.M., Yu, W., Combes, A.N., Little, M.H., Chianale, F., Primo, L., Serini, G., Mostov, K.E., Celani, A., Gamba, A., 2013. Polarity, cell division, and out-of-equilibrium dynamics control the growth of epithelial structures. J Cell Biol 203, 359-372.

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: No

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Dear Dr. Furusawa,

We are pleased to inform you that your manuscript 'Adhesion and polarity-driven morphogenesis: Mechanisms and constraints in tissue formation' has been provisionally accepted for publication in PLOS Computational Biology.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology.

Best regards,

Attila Csikász-Nagy

Academic Editor

PLOS Computational Biology

Stacey Finley

Section Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #2: The authors have addressed all the concerns raised in my review.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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Reviewer #2: No