The importance of intermediate filaments in the shape maintenance of myoblast model tissues
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Evaluation Summary:
Nagle and colleagues studied the determinants of key physical properties of multicellular assemblies, using magnetic flattening of spheroids. Their key and insightful result is that intermediate filaments could also be implicated in the setting the elastic properties of these assemblies, shedding light on this central cellular component and how their modifications could be important to the understanding of some pathologies. The paper would be strengthened by additional experiments to better support the claims.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
Liquid and elastic behaviours of tissues drive their morphology and response to the environment. They appear as the first insight into tissue mechanics. We explore the role of individual cell properties on spheroids of mouse muscle precursor cells and investigate the role of intermediate filaments on surface tension and Young’s modulus. By flattening multicellular myoblast aggregates under magnetic constraint, we measure their rigidity and surface tension and show that they act as highly sensitive macroscopic reporters closely related to microscopic local tension and effective adhesion. Shedding light on the major contributions of acto-myosin contractility, actin organization, and intercellular adhesions, we reveal the role of a major component of intermediate filaments in the muscle, desmin and its organization, on the macroscopic mechanics of these tissue models. Implicated in the mechanical and shape integrity of cells, intermediate filaments are found to be crucial to the mechanics of unorganized muscle tissue models even at an early stage of differentiation both in terms of elasticity and surface tension.
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Evaluation Summary:
Nagle and colleagues studied the determinants of key physical properties of multicellular assemblies, using magnetic flattening of spheroids. Their key and insightful result is that intermediate filaments could also be implicated in the setting the elastic properties of these assemblies, shedding light on this central cellular component and how their modifications could be important to the understanding of some pathologies. The paper would be strengthened by additional experiments to better support the claims.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This article examines how individual cell properties govern the mechanics of spheroids of muscle precursor cells. For this, the authors develop an automated approach that allows to measure the surface tension and elasticity of mm sized aggregates. Through drug treatments and genetic manipulations, they then attempt to link change in single cell mechanics to changes in aggregate mechanics. They suggest that desmin aggregation leads to an increase in surface tension and elasticity. Understanding the relationship between tissue mechanics, single cell mechanics, and cytoskeletal organisation is a topical subject and the role of intermediate filaments remains less well explored. Most of the results are confirmatory but the role of desmins is novel.
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Reviewer #2 (Public Review):
In their study, Nagle and colleagues aim at understanding what molecular determinants would set the rheological properties of multicellular assemblies. To this end, they used magnetic flattening of spheroids, a technique the group masters (Mazuel, Phys Rev Lett, 2015), which has the double advantage of probing the physical properties of spheroids while retaining the capability to retrieve the sample to perform additional experiments. They coupled magnetic flattening with staining of cryosections of spheroids, which allowed them to investigate how rheological properties can emerge from molecular characteristics. In particular, they set out to investigate the role of an important intermediate filament, desmin.
I find that the coupling of imaging techniques with rheological measurements is very interesting, and …
Reviewer #2 (Public Review):
In their study, Nagle and colleagues aim at understanding what molecular determinants would set the rheological properties of multicellular assemblies. To this end, they used magnetic flattening of spheroids, a technique the group masters (Mazuel, Phys Rev Lett, 2015), which has the double advantage of probing the physical properties of spheroids while retaining the capability to retrieve the sample to perform additional experiments. They coupled magnetic flattening with staining of cryosections of spheroids, which allowed them to investigate how rheological properties can emerge from molecular characteristics. In particular, they set out to investigate the role of an important intermediate filament, desmin.
I find that the coupling of imaging techniques with rheological measurements is very interesting, and allows the authors, with clever drug treatments, to partly disentangle the various key cellular parameters that are known to define the rheological properties of spheroids (effective adhesion or cortical tension). I also found the results with desmin appealing: linking intermediate filaments to rheological properties will allow the community to also explore their role in these emerging parameters.
That said, there are a number of unclear experimental procedures that limit the extent of the authors' claims. In particular, two key points lack detail: (i) the determination of the angle between cells, which is of utmost importance to disentangle effective adhesion from cortical tension, and (ii) the role of heat shock on the control and in general on the aforementioned parameters to understand how desmin could impact the rheological properties.
If these points are clarified, I am convinced that this study will shed new light onto the determinants of rheological properties, as well as provide new insights on the role of intermediate filaments like desmin, and how some mutations can lead to some pathologies.
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Reviewer #3 (Public Review):
This study demonstrates that the formation of desmin aggregates results in an increased surface tension and increased Young's modulus of C2C12 myoblast spheroids. This result is in line with data from single cell measurements and muscle tissues reported by other groups.
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