Stochastic cell-intrinsic stem cell decisions control colony growth in planarians
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eLife Assessment
This manuscript establishes a mathematical model to estimate the key parameters that control the repopulation of planarian stem cells after sublethal irradiation as they undergo fate-switching as part of their differentiation and self-renewal process. The findings are valuable for future investigation of stem cell division in planarians. The methods are solid, integrating modeling with perturbations of key transcription factors known to be critical for cell fate decisions, but the authors have only shown that this is the case for a small number of stem cell types.
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Abstract
Stem cells contribute to organismal homeostasis by balancing division, self-renewal and differentiation. Elucidating the strategies by which stem cells achieve this balance is critical for understanding homeostasis, and for addressing pathogenesis associated with the disruption of this balance (e.g., cancer). Planarians, highly regenerative flatworms, use pluripotent stem cells called neoblasts to maintain and regrow organs. A single neoblast can rescue an entire animal depleted from stem cells and regenerate all cell lineages. How neoblast differentiation and clonal expansion are governed to produce all the required cell types is unclear. Here, we integrated experimental and computational approaches to develop a quantitative model revealing basic principles of clonal growth of individual neoblasts. By experimentally suppressing differentiation to major lineages, we elucidated the interplay between colony growth and lineage decisions. Our findings suggest that neoblasts pre-select their progenitor lineage based on a cell-intrinsic fate distribution. Arresting differentiation into specific lineages disrupts neoblast proliferative capacity without inducing compensatory expression of other lineages. Our analysis of neoblast colonies is consistent with a cell-intrinsic decision model that can operate without memory or communication between neoblasts. This simple cell fate decision process breaks down in homeostasis, likely because of the activity of feedback mechanisms. Our findings uncover essential principles of stem cell regulation in planarians, which are distinct from those observed in many vertebrate models. These mechanisms enable robust production of diverse cell types, and facilitate regeneration of missing tissues.
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eLife Assessment
This manuscript establishes a mathematical model to estimate the key parameters that control the repopulation of planarian stem cells after sublethal irradiation as they undergo fate-switching as part of their differentiation and self-renewal process. The findings are valuable for future investigation of stem cell division in planarians. The methods are solid, integrating modeling with perturbations of key transcription factors known to be critical for cell fate decisions, but the authors have only shown that this is the case for a small number of stem cell types.
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Reviewer #1 (Public review):
Summary:
This is a very creative study using modeling and measurement of neoblast dynamics to gain insight into the mechanism that allows these highly potent cells to undergo fate-switching as part of their differentiation and self-renewal process. The authors estimate growth equation parameters for expanding neoblast clones based on new and prior experimental observations. These results indicate neoblast likely undergo much more symmetric self-amplifying division than loss of the population through symmetric differentiation, in the case of clone expansion assays after sublethal irradiation. Neoblasts take on multiple distinct transcriptional fates related to their terminally differentiated cell types, and prior work indicated neoblasts have a high plasticity to switch fates in a way linked to cell cycle …
Reviewer #1 (Public review):
Summary:
This is a very creative study using modeling and measurement of neoblast dynamics to gain insight into the mechanism that allows these highly potent cells to undergo fate-switching as part of their differentiation and self-renewal process. The authors estimate growth equation parameters for expanding neoblast clones based on new and prior experimental observations. These results indicate neoblast likely undergo much more symmetric self-amplifying division than loss of the population through symmetric differentiation, in the case of clone expansion assays after sublethal irradiation. Neoblasts take on multiple distinct transcriptional fates related to their terminally differentiated cell types, and prior work indicated neoblasts have a high plasticity to switch fates in a way linked to cell cycle progression and possibly through a random process. Here, the authors explore the impact of inhibition of key transcription factors defining such states (ie "fate specifying transcription factors", FSTFs) plus measurement and modeling in the clone expansion assay, to find that inhibition of factors like zfp1 likely cause otherwise zfp1-fated neoblasts to fail to proliferate and differentiation without causing compensatory gains in other lineages. A mathematical model of this process assuming that neoblasts do not retain a memory of prior states while they proliferate, and transition across specified states can mimic the experimentally determined decreased sizes of clones following inhibition of zfp1. Complementary approaches to inhibit more than one lineage (muscle plus intestine) supports the idea that this is a more general process in planarian stem cells. These results provide an important advance for understanding the fate-switching process and its relationship to neoblast growth.
Overall I find the evidence very well presented and the study compelling. It offers an important new perspective on the key properties of neoblasts. I do have some comments to clarify the presentation and significance of the work.
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Reviewer #2 (Public review):
Summary:
Cell cycle duration and cell fate choice are critical to understanding the cellular plasticity of neoblasts in planarians. In this study, Tamar et al. integrated experimental and computational approaches to simulate a model for neoblast behaviors during colony expansion.
Strengths:
The finding that "arresting differentiation into specific lineages disrupts neoblast proliferative capacities without inducing compensatory expression of other lineages" is particularly intriguing. This concept could inspire further studies on pluripotent stem cells and their application for regenerative biology.
Weaknesses:
However, the absence of a cell-cell feedback mechanism during colony growth and the likelihood of the difference needs to be clarified. Is there any difference in interpreting the results if this …
Reviewer #2 (Public review):
Summary:
Cell cycle duration and cell fate choice are critical to understanding the cellular plasticity of neoblasts in planarians. In this study, Tamar et al. integrated experimental and computational approaches to simulate a model for neoblast behaviors during colony expansion.
Strengths:
The finding that "arresting differentiation into specific lineages disrupts neoblast proliferative capacities without inducing compensatory expression of other lineages" is particularly intriguing. This concept could inspire further studies on pluripotent stem cells and their application for regenerative biology.
Weaknesses:
However, the absence of a cell-cell feedback mechanism during colony growth and the likelihood of the difference needs to be clarified. Is there any difference in interpreting the results if this mechanism is considered? More explanation and discussion should be included to distinguish the stages controlled by the one-step model from those discussed in this study. Although hnf-4 and foxF have been silenced together to validate the model, a deeper understanding of the tgs-1+ cell type and the non-significant reduction of tgs-1+ neoblasts in zfp-1 RNAi colonies is necessary, considering a high neural lineage frequency.
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Author response:
Reviewer #1:
Overall I find the evidence very well presented and the study compelling. It offers an important new perspective on the key properties of neoblasts. I do have some comments to clarify the presentation and significance of the work.
We thank the reviewer for the positive feedback and plan to improve the presentation of the work.
Reviewer #2:
However, the absence of a cell-cell feedback mechanism during colony growth and the likelihood of the difference needs to be clarified. Is there any difference in interpreting the results if this mechanism is considered?
We will improve the description of the model assumptions and the interpretation of the data on the basis of these assumptions.
Although hnf-4 and foxF have been silenced together to validate the model, a deeper understanding of the tgs-1+ cell type …
Author response:
Reviewer #1:
Overall I find the evidence very well presented and the study compelling. It offers an important new perspective on the key properties of neoblasts. I do have some comments to clarify the presentation and significance of the work.
We thank the reviewer for the positive feedback and plan to improve the presentation of the work.
Reviewer #2:
However, the absence of a cell-cell feedback mechanism during colony growth and the likelihood of the difference needs to be clarified. Is there any difference in interpreting the results if this mechanism is considered?
We will improve the description of the model assumptions and the interpretation of the data on the basis of these assumptions.
Although hnf-4 and foxF have been silenced together to validate the model, a deeper understanding of the tgs-1+ cell type and the non-significant reduction of tgs-1+ neoblasts in zfp-1 RNAi colonies is necessary, considering a high neural lineage frequency.
We will improve the analysis of this result in light of the experimentally determined frequency of the tgs-1+ neoblast population.
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