Piezo1 Mediates Keratinocyte Mechanotransduction

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

doi:10.1101/2020.07.19.211086

Cited by 14 publications

(20 citation statements)

References 26 publications

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“…The Krt14Cre mouse line was crossed with Piezo1 fl/fl mice (Cahalan et al 2015) to generate Krt14Cre;Piezo1 fl/fl mice (hereafter referred to as conditional knockout, cKO) which are viable and develop normally ( Supplementary Fig. 1), consistent with observations by Moehring et al (Moehring et al 2020). qRT-PCR analysis using keratinocytes harvested from Piezo1 cKO and littermate control animals confirmed the expression of Piezo1 but not Piezo2 in control mice ( Supplementary Fig.…”

Section: Reduced Piezo1 Accelerates Wound Healingsupporting

confidence: 67%

“…Perhaps, there is an advantage to slower healing in the presence of PIEZO1, or the channel is important for other functions in keratinocytes. Consistent with this idea, a recent study by Moehring et al reports that keratinocyte PIEZO1 is critical for sensory afferent firing and behavioral responses to innocuous and noxious mechanical stimulation (Moehring et al 2020).…”

Section: Discussionmentioning

confidence: 83%

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Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing

Holt

Zeng

Evans

et al. 2020

Preprint

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Keratinocytes are the predominant cell type of the epidermis and form an important protective barrier to the external environment. During the healing of wounded skin, keratinocytes migrate from the wound edge to reinstate the epithelial barrier. Mechanical cues are important regulators of cell migration in this process; however, the molecular transducers and biophysical mechanisms of this mechanoregulation remain elusive. Here, we show through molecular, cellular and organismal studies that the mechanically-activated ion channel PIEZO1 regulates keratinocyte migration through dynamic cellular localization which dictates retraction events. Single keratinocytes isolated from an epidermal-specific _Piezo1_ knockout mouse moved faster and migrated farther than littermate controls. To determine how PIEZO1 may contribute to cell migration, we imaged the localization of endogenous channels in migrating keratinocytes over several hours. We found that enrichment of PIEZO1 channel puncta correlated with cellular retraction in migrating single cells and in collectively migrating monolayers. Strikingly, PIEZO1 activation with Yoda1 resulted in increased retraction events in single cells as well as in monolayers of keratinocytes. During in vitro scratch assays, Yoda1-induced activation of PIEZO1 caused slower wound closure due to increased retraction events at the wound. Conversely, channel deletion resulted in faster scratch wound closure. This result was mirrored in vivo whereby epidermal-specific PIEZO1 knockout mice exhibited faster wound closure compared to littermate controls, and epidermal-specific PIEZO1 gain-of-function mice displayed slower wound closure. Overall, our findings show that reducing Piezo1 activity can accelerate wound healing, suggesting a potential pharmacological target for wound treatment. More broadly, we show that molecular-scale spatiotemporal dynamics of Piezo1 channels controls tissue-scale cell migration, a cellular process of fundamental importance in development, homeostasis and repair.

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Section: Reduced Piezo1 Accelerates Wound Healingsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 83%

Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing

Holt

Zeng

Evans

et al. 2020

Preprint

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“…Ablation of Piezo2 selectively in DRG neurons in vivo with Piezo1expression intact [68] abolishes MA-currents and reduces mechanical hypersensitivity induced by peripheral nerve injury [51,75]. Moreover, specific Piezo1 deletion in skin keratinocytes that naturally express both Piezo1/2 induces significant reduction of responses to non-noxious and noxious mechanical stimuli [50]. These observations together imply that Piezo1/2 do not simply serve a redundant or complementary role for each other in mechanotransduction.…”

Section: Discussionmentioning

confidence: 97%

“…Piezo1 is highly expressed in skin [18], and has been detected in keratinocytes [31,50] and sensory afferent lanceolate endings [98]. We here characterized Piezo1 protein expression profile in rat hindpaw skin (Fig.…”

Section: Detection Of Piezo1-ir In Sciatic Nerve Spinal Cord and Skinmentioning

confidence: 99%

“…Systemic administration of a Piezo1-inhibiting tarantula spider toxin (GsMTx4, a nonspecific Piezo1 antagonist) relieves mechanical hypersensitivity in mice from both peripheral nerve injury and inflammation [55], while intra-articular injection of GsMTx4 relieves hypersensitivity in osteoarthritic mice [30]. Finally, hindpaw intradermal Yoda1 causes prolonged hyperalgesia [83] and paw attending responses [50] while injection of GsMTx4 reverses the mechanical hyperalgesia induced by intradermal injection of inflammatory mediators [3]. Although analgesic effects of GsMTx4 could be due to inhibition of multiple MSCs, these observations together suggest a possibility that Piezo1 may contribute to peripheral nerve nociceptive mechanobiology.…”

Section: Introductionmentioning

confidence: 99%

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Peripherally targeted analgesia via AAV-mediated sensory neuron-specific inhibition of multiple pronociceptive sodium channels in rat

Shin

Itson-Zoske

Fan

et al. 2021

Preprint

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Here, we present evidence showing Piezo1 expression in the primary sensory neurons (PSNs) and non-neuronal cells of rat peripheral nervous system. Using a knockdown/knockout validated antibody, we detected Piezo1 immunoreactivity (IR) in ~80% of PSNs of rat dorsal root ganglia (DRG) with higher IR density in the small- and medium-sized neurons, and within axons extending to both central presynaptic terminals innervating to the spinal dorsal horn and peripheral cutaneous sensory terminals in the skin. Piezo-IR was clearly identified in DRG perineuronal glia, including satellite glial cells (SGCs) and non-myelinating Schwann cells; in sciatic nerve Schwann cells surrounding the axons and cutaneous afferent endings; and in skin epidermal Merkel cells and melanocytes. Neuronal and non-neuronal Piezo1 channels were functional, since various cells (dissociated PSNs and SGCs from DRGs, isolated Schwann cells, and primary human melanocytes) exhibited a robust response to Piezo1 agonist Yoda1 by an increase of intracellular Ca2+ concentration ([Ca2+]i). These responses were abolished by Piezo1 antagonist GsMTx4. Immunoblots showed elevated Piezo1 protein in DRG proximal to peripheral nerve injury-induced painful neuropathy, while PSNs and SGCs from rats with neuropathic pain showed greater Yuda1-evoked elevation of [Ca2+]i and an increased frequency of cells responding to Yoda1, compared to controls. Ipsilateral sciatic nerve application of GsMTx4 alleviated mechanical hypersensitivity following nerve injury. Overall, our data show that Piezo1 is widely expressed by the neuronal and non-neuronal cells in the peripheral sensory pathways and that painful nerve injury is associated with activation of Piezo1 in PSNs and peripheral glia cells.

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