Keratinocyte PIEZO1 modulates cutaneous mechanosensation

Mikesell, Alexander R.; Isaeva, Elena; Moehring, Francie; Sadler, Katelyn E.; Menzel, A.; Stucky, Cheryl L.

doi:10.7554/elife.65987

Cited by 41 publications

(50 citation statements)

References 66 publications

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“…However, in addition to Piezo2, other factors are likely to contribute to the distinct mechanical thresholds, adaptation properties, and responsivity to hair deflection and vibratory stimuli of the distinct LTMR and HTMR subtypes. Additional determinants of mechanoresponsivity include the axonal structures and other cellular constituents of mechanosensory end organs 1 , skin arborization patterns (Figure 2), the ion channel determinants of intrinsic excitability 37 , modulation by non-neuronal cells 65,[91][92][93][94][95][96] , expression of Piezo1 97 , and other potential mechanosensitive molecules and auxiliary proteins [98][99][100][101] .…”

Section: Molecular Basis Of Drg Neuron Response Propertiesmentioning

confidence: 99%

A DRG genetic toolkit reveals molecular, morphological, and functional diversity of somatosensory neuron subtypes

Iskols

Shi

et al. 2023

Preprint

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Mechanical and thermal stimuli acting on the skin are detected by morphologically and physiologically distinct sensory neurons of the dorsal root ganglia (DRG). Achieving a holistic view of how this diverse neuronal population relays sensory information from the skin to the central nervous system (CNS) has been challenging with existing tools. Here, we used transcriptomic datasets of the mouse DRG to guide development and curation of a genetic toolkit to interrogate transcriptionally defined DRG neuron subtypes. Morphological analysis revealed unique cutaneous axon arborization areas and branching patterns of each subtype. Physiological analysis showed that subtypes exhibit distinct thresholds and ranges of responses to mechanical and/or thermal stimuli. The somatosensory neuron toolbox thus enables comprehensive phenotyping of most principal sensory neuron subtypes. Moreover, our findings support a population coding scheme in which the activation thresholds of morphologically and physiologically distinct cutaneous DRG neuron subtypes tile multiple dimensions of stimulus space.

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Section: Molecular Basis Of Drg Neuron Response Propertiesmentioning

confidence: 99%

A DRG genetic toolkit reveals molecular, morphological, and functional diversity of somatosensory neuron subtypes

Iskols

Shi

et al. 2023

Preprint

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“…Their activation in response to tensile forces applied to the cell membrane allows calcium to pass across a gradient into the cytoplasm activating signaling cascades that influence cell adhesion and keratinocyte differentiation 90,91 . Piezo1, a family member of the mechanosensitive cation channels, which is also expressed in epidermal keratinocytes, has previously been implicated in mediating keratinocyte mechanical sensitivity and migration during wound healing 92,93 . Interestingly, Piezo1 activity appears to influence several intracellular processes through modulation of cytoskeletal dynamics and cell adhesion 94 .…”

Section: Discussionmentioning

confidence: 99%

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

Huang

Kuri

Zou

et al. 2022

Preprint

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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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“…Keratinocytes are the first point of contact we have with our external environment. They are proximal to sensory nerve terminals, 1,56,63,74 make synapse-like connections with these terminals, 107 are involved in peripheral somatosensation, 70,71 and mediate peripheral neuron activity. 14,70 As such, they are well-suited to be involved in hypersensitivity in SCD, and in fact, our calcium imaging data suggest they may play a role in TRPV4mediated SCD hypersensitivity.…”

Section: Keratinocytes As a Novel Cell Type In Sickle Cell Disease Hy...mentioning

confidence: 99%

Peripheral transient receptor potential vanilloid type 4 hypersensitivity contributes to chronic sickle cell disease pain

Ehlers¹,

Sadler²,

Stucky³

2023

PAIN

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Debilitating pain affects the lives of patients with sickle cell disease (SCD). Current pain treatment for patients with SCD fail to completely resolve acute or chronic SCD pain. Previous research indicates that the cation channel transient receptor potential vanilloid type 4 (TRPV4) mediates peripheral hypersensitivity in various inflammatory and neuropathic pain conditions that may share similar pathophysiology with SCD, but this channel's role in chronic SCD pain remains unknown. Thus, the current experiments examined whether TRPV4 regulates hyperalgesia in transgenic mouse models of SCD. Acute blockade of TRPV4 alleviated evoked behavioral hypersensitivity to punctate, but not dynamic, mechanical stimuli in mice with SCD. TRPV4 blockade also reduced the mechanical sensitivity of small, but not large, dorsal root ganglia neurons from mice with SCD. Furthermore, keratinocytes from mice with SCD showed sensitized TRPV4-dependent calcium responses. These results shed new light on the role of TRPV4 in SCD chronic pain and are the first to suggest a role for epidermal keratinocytes in the heightened sensitivity observed in SCD.

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Keratinocyte PIEZO1 modulates cutaneous mechanosensation

Cited by 41 publications

References 66 publications

A DRG genetic toolkit reveals molecular, morphological, and functional diversity of somatosensory neuron subtypes

A DRG genetic toolkit reveals molecular, morphological, and functional diversity of somatosensory neuron subtypes

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

Peripheral transient receptor potential vanilloid type 4 hypersensitivity contributes to chronic sickle cell disease pain

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