Peer review process
Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, public reviews, and a provisional response from the authors.
Read more about eLife’s peer review process.Editors
- Reviewing EditorCarolyn AdlerCornell University, Ithaca, United States of America
- Senior EditorDidier StainierMax Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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.
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.
