Stress vesicles are induced by acute mechanical force and precede the commitment of epidermal stem cells to terminal differentiation

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The skin has a pronounced ability to adapt to physical changes in the environment by exhibiting plasticity at the cellular level. Transient mechanical deformations applied to the skin are accommodated without permanent changes to tissue structure. However, sustained physical stress induces long-lasting alterations in the skin, which are mediated by shifts in the fates of epidermal stem cells. To investigate this phenomenon, we implemented two-photon intravital imaging to capture the responses of epidermal cells when an acute mechanical force is applied to the live skin. We show that mechanical stress induces the formation of intracellular vesicles in epidermal stem cells, which are filled with extracellular fluid and gradually enlarge, causing the deformation of the cell nucleus. By lineage tracing analysis we demonstrate that the degree of nuclear deformation is linked to cell fate. Utilizing a fluorescent in vivo reporter, to capture intracellular calcium dynamics, we show that mechanical force induces a sustained increase in intracellular calcium within basal epidermal stem cells. Conditional deletion of Piezo1, a mechanosensitive ion channel, alters intracellular calcium dynamics and increases the number of stress vesicles in epidermal stem cells. Using a human skin xenograft model, we show that stress vesicles are a conserved phenomenon in mammalian skin. This study uncovers stress vesicles as key manifestations of the mechanism that regulates the fate of epidermal stem cells under conditions of mechanical stress, in which Piezo1 and calcium dynamics are also involved.

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    In this manuscript, the authors reported the formation of intracellular stress vesicles upon mechanical stress. These vesicles are enclosed in a lipid bilayer and contain extracellular fluid and enlarge gradually involving contractile actomyosin cytoskeleton leading to deformation of nucleus. Collectively these changes lead to regulation of cell fate of the basal layer keratinocytes through sustained increase in intracellular calcium gradient mediated by mechanosensitive ion channel PIEZO1.


    ·       This study employed robust and systemic approaches to understand the response of different cell layers in the skin epidermis focusing on the changes in collective cell behavior rather than individual cells by utilizing in vivo mouse models upon acute and sustained mechanical stress.

    ·       The authors reported careful observations of multiple parameters of the stressed cells upon mechanical stress and thoroughly investigated the possible links with different known factors involved in mechanosensing and mechanotransduction processes.

    ·       The authors used advanced tools to apply different forms of mechanical stress, characterize the stress vesicles and to understand the cell fate regulation, intracellular calcium dynamics in live cells and used mouse models necessary for the study.

    ·       Other than mouse skin the authors have also look at the effect of acute and sustained mechanical stress on human xenograft model confirming this as a conserved phenomenon in mammalian skin.


    ·       The authors employed three independent techniques to exert acute mechanical force in the form of negative (suction) and positive (compression) pressure and stretching (lateral tension) onto the mouse skin epidermis. However, the authors discuss whether the cellular effects of these mechanical cues are similar or different. Considering multiple literature suggest diverse cellular effect upon compression, shear force and tension release, it would be interesting to know whether there are differential cellular responses upon these three forms of mechanical stresses.

    ·       Formation of phospholipid stress vesicles in different cell types upon mechanical and osmotic stress is already known. The authors might consider summarizing the past findings about mechanical stress induced vesicles and give a brief introduction about current understanding in the field by citing relevant literature.

    ·       The authors observed high concentration of Myosin, Vinculin and F-actin surrounding the stress vesicles and implicated the role of contractile actomyosin cytoskeleton in the formation and/or growth of stress vesicles in epidermal stem cells. However, the detailed mechanism how mechanical stress is perceived by the actomyosin cytoskeleton network and how actomyosin cytoskeleton in turn regulate the stress vesicle formation is not deciphered in this study. Authors might consider delving into the detailed mechanism how actomyosin cytoskeleton can be impacted upon mechanical stress thereby leading to formation of the stress vesicles.

    ·       The authors have identified a link between stress vesicle formation and degree of nuclear deformation. However, they have only considered the Lamin A/C as key component of nuclear architecture and did not observe any changes in the expression of the same upon mechanical stress condition. However, there are many other components of nuclear envelope and lamina that sense and transduce mechanical cues in the form of nuclear deformation and lead to changes in mechanoresponsive gene regulation. Authors might want to consider understanding the potential role of any nuclear components that might functionally link nuclear deformation with stress vesicle formation.

    ·       The authors have reported the changes in the cell fate upon mechanical stress. However, the detailed mechanism that collectively lead to these changes are not deciphered in this manuscript. While authors analysed the transcriptional changes in PIEZO cKO mouse and suggested its role in cell fate regulation and mechanotransduction pathways. However, whether these changes are similar to broad spectrum mechanical stress (compression, tension and shear forces) are not clear. The authors might consider looking at the changes in gene expression level after mechanical stress and establish a potential link between the mechanical cues and downstream phenomena such as stress vesicle formation and nuclear envelope deformation leading to cell fate regulation.

    Competing interests

    The author declares that they have no competing interests.