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Membrane tension mediated mechanotransduction drives fate choice in embryonic stem cells

Henry De Belly, Philip H. Jones, Ewa K. Paluch, Kevin J. Chalut

Preprint posted on 9 October 2019 https://www.biorxiv.org/content/10.1101/798959v1

Article now published in Cell Stem Cell at http://dx.doi.org/10.1016/j.stem.2020.10.018

and

Cell surface mechanics gate stem cell differentiation

Martin Bergert, Sergio Lembo, Danica Milovanović, Mandy Börmel, Pierre Neveu, Alba Diz-Muñoz

Preprint posted on 9 October 2019 https://www.biorxiv.org/content/10.1101/798918v1

Fate choice at the cell’s edge: Two complimentary preprints show that plasma membrane tension regulates stem cell fate

Selected by Joseph Jose Thottacherry

Background:

Stem cell differentiation is typically associated with shape changes, indicating that mechanics play a role in this transition. Although substrate mechanics and cell adhesion are known to play a role in this transition, the role of intrinsic cellular mechanics is not understood. Two papers on bioRxiv try to understand the relation between shape changes and stem cell differentiation.

Key findings:

De Belly et al.1 observe that when naive pluripotent mouse embryonic stem cells (ES) undergo differentiation, they change shape from round to spread. By following the cells during this transition, the authors find that there is a transient blebbing of plasma membrane before the cells spread. Blebbing happens due to detachment of the plasma membrane from the underlying cytoskeleton and indicates changes in plasma membrane mechanics. The authors go on to check if this has any relevance for the differentiation of the ES cells. Using optical tweezers to measure static tether forces, they find that the round/naive pluripotent cells show higher tension than the spread/differentiated cells. So how does the cell regulate the attachment between membrane and cytoskeleton? The authors find that the cells downregulate membrane-cortex attachments (MCA) upon exiting the pluripotent state and this is mediated through a GSK3/b-catenin mediated mechanism. The increase in tension is sufficient since increasing the MCA increases the membrane tension and abrogates the exit from naive pluripotency. Importantly, this decrease in tension upregulates endocytosis  of FGFR1, which the authors also test with functional experiments. This mechanically-induced endocytosis leads to an increase in FGF/ERK signalling that is required for the exit from pluripotency.

Image reproduced from De Belly et al.1 with permission.

Bergert et al.2 make very similar findings using complementary approaches. Here the authors measure static tether force using single cell force spectroscopy and also find that the forces decrease upon exiting from the naive pluripotent state. However, static tether force measurements are complicated to interpret since they have components of in-plane membrane tension and MCA that contributes to apparent membrane tension. While the De Belly et al. paper indicated the change in apparent membrane tension could be due to changes in MCA through ERM proteins, Bergert et al. use dynamic tether pulling measurements to confirm that the decrease in apparent membrane tension is due to a decrease in MCA. Bergert et al. increased the MCA by expressing an active version of an ERM protein and this increase in membrane tension blocks the exit from naive pluripotency. Further, they make a synthetic linker that would increase MCA but would be biochemically silent and show that increase in membrane tension, by upregulating MCA, is sufficient to prevent cells from exiting naive pluripotency.

What I like about these preprints:

It is good to see similar results using multiple methods from independent laboratories and this shows the robustness of this process. Life has evolved obeying and utilizing physical laws. While there are many papers showing how external mechanics regulate stem cell fate, these preprints show that intrinsic regulation of physical parameters could regulate biochemical pathways to regulate cellular fate. Signalling networks that are characterized are mostly biochemical, but these papers show that a physical parameter could bridge two different biochemical signalling networks. Here, GSK3/Beta catenin mediated decrease of membrane tension activates FGF/ERK signalling by upregulating FGF receptor endocytosis, thus bringing a coordination between these two essential pluripotency regulators. Multiple mechanistic processes depend on changes to membrane tension and the inert linker developed by Bergert et al. helps differentiate the effects of in-plane tension and MCA in these contexts and could be a helpful tool for many in the field.

Questions for the authors:

1) On exiting naive pluripotency, the cells show blebbing followed by lower membrane tension and increased endocytosis. Does it mean there is a new steady state tension for differentiated cells? How long is this new tension level maintained? The increased endocytosis could increase the membrane tension, so could there be increased exocytosis to maintain this new steady state?

2) Could this endocytic mechanism be specific for uptake of FGFR1 or is there a general reduction in other cell surface receptors that could play a role here?

References:

1. Belly, H. D., Jones, P. H., Paluch, E. K. & Chalut, K. J. Membrane tension mediated mechanotransduction drives fate choice in embryonic stem cells. Biorxiv 798959 (2019) doi:10.1101/798959.

2. Bergert, M. et al. Cell surface mechanics gate stem cell differentiation. Biorxiv 798918 (2019) doi:10.1101/798918.

3. Palamidessi, A. et al. Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma. Nat Mater 18, 1252–1263 (2019).

Tags: cell fate, differentiation, membrane tension, stem cells

Posted on: 25 February 2020

doi: https://doi.org/10.1242/prelights.17242

(2 votes)

Author's response

Henry De Belly, Ewa Paluch and Kevin Chalut shared about Membrane tension mediated mechanotransduction drives fate choice in embryonic stem cells

1) On exiting naive pluripotency, the cells show blebbing followed by lower membrane tension and increased endocytosis. Does it mean there is a new steady state tension for differentiated cells? How long is this new tension level maintained? The increased endocytosis could increase the membrane tension, so could there be increased exocytosis to maintain this new steady state?

Henry De Belly, Ewa Paluch & Kevin Chalut : It is tempting to say that these cells have found a new steady state of membrane tension. However, exit from naïve pluripotency is a transient process; therefore, we cannot conclude if this is a new steady state or a temporary change as it is difficult to state what would constitute a steady state in such a transient context.

We suspect that the increase in endocytosis coincides with an increase in exocytosis. But it remains to be tested. It would be interesting to know how that relates to maintaining a steady state of membrane tension.

2) Could this endocytic mechanism be specific for uptake of FGFR1 or is there a general reduction in other cell surface receptors that could play a role here?

Henry De Belly, Ewa Paluch & Kevin Chalut : This is an excellent question; we chose to focus on FGFR1 uptake as it is known to regulate the activity of ERK during the exit from naïve pluripotency. However, there is every reason to believe that this mechanism would apply to uptake of other receptors besides FGFR1. Indeed, previous work, notably by the laboratory of Emmanuel Farge, have shown that endocytosis can regulate various signalling pathways during fate transitions.

 Endocytosis has long been seen as a negative regulator of most signalling pathways as it increases the recycling rate of cell surface receptors. However, it has also been shown that in some specific pathways, such as EGFR/FGFR-ERK (see doi: 10.1038/s41563-019-0425-1)3, endocytosis of the receptor is required to allow the recruitment of essential signalling co-factors. Thus, endocytosis has a dual regulatory role as it can positively regulate some signalling pathways and negatively regulate others. As such changes in endocytosis can globally regulate signalling in cells.

 This is especially interesting as it suggests the fact that changes in membrane tension could be used by cells as a way to globally affect many signalling pathways at once, something that is particularly relevant during fate transitions. We thus speculate that changes in membrane tension could be used as a global gating mechanism to regulate intracellular signalling and therefore cell fate choices.

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