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Mechanically-driven Stem Cell Separation in Tissues caused by Proliferating Daughter Cells

by Johannes C. Krämer, Edouard Hannezo, Gerhard Gompper, Jens Elgeti

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Submission summary

Authors (as registered SciPost users): Jens Elgeti · Johannes C. Krämer
Submission information
Preprint Link: https://arxiv.org/abs/2310.04272v1  (pdf)
Date submitted: 2023-10-09 08:07
Submitted by: Elgeti, Jens
Submitted to: SciPost Physics
Ontological classification
Academic field: Physics
Specialties:
  • Biophysics
Approaches: Theoretical, Computational

Abstract

The homeostasis of epithelial tissue relies on a balance between the self-renewal of stem cell populations, cellular differentiation, and loss. Although this balance needs to be tightly regulated to avoid pathologies, such as tumor growth, the regulatory mechanisms, both cell-intrinsic and collective, which ensure tissue steady-state are still poorly understood. Here, we develop a computational model that incorporates basic assumptions of stem cell renewal into distinct populations and mechanical interactions between cells. We find that the model generates unexpected dynamic features: stem cells repel each other in the bulk tissue and are thus found rather isolated, as in a number of in vivo contexts. By mapping the system onto a gas of passive Brownian particles with effective repulsive interactions, that arise from the generated flows of differentiated cells, we show that we can quantitatively describe such stem cell distribution in tissues. The interaction potential between a pair of stem cells decays exponentially with a characteristic length that spans several cell sizes, corresponding to the volume of cells generated per stem cell division. Our findings may help understanding the dynamics of normal and cancerous epithelial tissues.

Current status:
Has been resubmitted


Submission & Refereeing History

Resubmission scipost_202402_00001v2 on 13 February 2024

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Submission 2310.04272v1 on 9 October 2023

Reports on this Submission

Anonymous Report 2 on 2023-12-5 (Invited Report)

Strengths

In this manuscript Kramer et al. considered a mechanistic model for stem cell separation in tissue homeostasis, based on the two-particle cell model [7].

Tissue homeostasis is the state where cell differentiation, division, and apoptosis are all balanced with each other. In order for this to happen, the stem cells have to be scattered homogeneously throughout the tissue. Several mechanisms for this stem cell separation have been proposed, but most of them are based on local chemical reactions. In this manuscript, the authors proposed an alternative mechanistic based explanation, which comes rather naturally from the concept of `homeostatic pressure' [7,17], coupled to a simple model of cell differentiation [12]. In particular, they found a clustering of progeny cells around a stem cell, which gives an effective repulsion between the stem cells.

I think the results are interesting and provide a new insight into tissue homeostasis.

Weaknesses

Although the analysis of the effective repulsion from the pair distribution function seems to be valid, I have skepticism about the reported `effective propulsion' of the stem cells, near the boundary of tissues.

Report

Due to the weakness above, I hesitate to recommend publications of the manuscript before substantial revision and addressing my concerns below:

Requested changes

Major comments:
1. Is there any reason why Newtonian dynamics (rather than overdamped dynamics) is used? (also related to the comment below)

2. The mechanism for effective propulsion is not explained clearly. I am not sure if this propulsion is due to inertial effects, in which case the crossover timescale from ballistic to diffusive regime will correspond to the inertial timescale of the particles/cells. I think the authors should repeat the measurements with overdamped dynamics to rule out that the effective propulsion is not due to the inertial regime of the dynamics.

3. Many models of epithelial tissues, on the other hand, do include self-propulsion, since most epithelial cells are also motile. Perhaps comment on this.


Minor comments:
4. In the model the apoptosis rate of the SC cells is zero. Did you assume the apoptosis timescale for SC to be much longer than the simulation timescales?

5. Does the cell division conserve the centre of mass?

6. Page 4 paragraph 2: What is N_{TA}? is it the maximal number of division cycles?

7. Page 4 paragraph 2: ``Note that k_d is not fixed in our simulation model, but controlled by pressure''. What is the functional dependence of k_d on pressure?

8. Figure 2,3,4: are all the data taken at steady state?

9. In the model: The cell is composed of two particles. It seems that the only interaction between these two particles within the same cell is the active growth force, Eq. (2). In the case of TD cells, where growth force is zero, how do you prevent the two particles from separating?

10. In the model: What is the initial state of the two particles when a new cell is born?

11. Table 1: what do these numbers correspond to in physical units?

  • validity: good
  • significance: high
  • originality: high
  • clarity: ok
  • formatting: good
  • grammar: good

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