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The detection of mechanical qualities of foodstuffs is essential for nutrient acquisition, evaluation of food freshness, and bolus formation during mastication. However, the mechanisms through which mechanosensitive cells in the oral cavity transmit mechanical information from the periphery to the brain are not well defined. We hypothesized Merkel cells, which are epithelial mechanoreceptors and important for pressure and texture sensing in the skin, can be mechanically activated in the oral cavity. Using live-cell calcium imaging, we recorded Merkel cell activity in ex vivo gingival and palatal preparations from mice in response to mechanical stimulation. Merkel cells responded with distinct temporal patterns and activation thresholds in a region-specific manner, with Merkel cells in the hard palate having a higher mean activation threshold than those in the gingiva. Unexpectedly, we found that oral keratinocytes were also activated by mechanical stimulation, even in the absence of Merkel cells. This indicates that mechanical stimulation of oral mucosa independently activates at least two subpopulations of epithelial cells. Finally, we found that oral Merkel cells contribute to preference for consuming oily emulsion. To our knowledge, these data represent the first functional study of Merkel-cell physiology and its role in flavor detection in the oral cavity.

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Neuroendocrine carcinoma of the breast is a rare malignant tumor which, with the features of Merkel cells is even rarer. Herein, we report a case of small cell carcinoma with Merkel cell features in a 52-year-old female. Microscopically, the tumor was characterized by diffuse and consistent small round cells that were de-adherent. The tumor cells had round or oval nuclei with delicate chromatin and small nucleoli, the cytoplasm was sparse and eosinophilic. Additionally, the tumor was accompanied by high-grade ductal carcinoma in situ. Immunohistochemical staining showed that infiltrating tumor cells were positive for neuroendocrine markers, and punctately positive for CK20. The patient underwent modified radical mastectomy, axillary lymph node dissection, and postoperative adjuvant chemotherapy. No recurrence or metastasis was observed during follow-up period. Primary breast small cell carcinoma with Merkel cell features is rare and easily misdiagnosed as Merkel cell carcinoma. Early diagnosis and treatment may improve patient prognosis.

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Merkel cells (MCs) are rare multimodal epidermal sensory cells. Due to their interactions with slowly adapting type 1 (SA1) Aß low-threshold mechanoreceptor (Aß-LTMRs) afferents neurons to form Merkel complexes, they are considered to be part of the main tactile terminal organ involved in the light touch sensation. This function has been explored over time by ex vivo, in vivo, in vitro, and in silico approaches. Ex vivo studies have made it possible to characterize the topography, morphology, and cellular environment of these cells. The interactions of MCs with surrounding cells continue to be studied by ex vivo but also in vitro approaches. Indeed, in vitro models have improved the understanding of communication of MCs with other cells present in the skin at the cellular and molecular levels. As for in vivo methods, the sensory role of MC complexes can be demonstrated by observing physiological or pathological behavior after genetic modification in mouse models. In silico models are emerging and aim to elucidate the sensory coding mechanisms of these complexes. The different methods to study MC complexes presented in this review may allow the investigation of their involvement in other physiological and pathophysiological mechanisms, despite the difficulties in exploring these cells, in particular due to their rarity.

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As an essential component of mechano-gated ion channels, critically required for mechanotransduction in mammalian cells, PIEZO2 is known to be characteristically expressed by Merkel cells in human skin. Here, we immunohistochemically investigated the occurrence of Piezo channels in a case series of Merkel cell carcinoma. A panel of antibodies was used to characterize Merkel cells, and to detect PIEZO2 expression. All analyzed tumors displayed PIEZO2 in nearly all cells, showing two patterns of immunostaining: membranous and perinuclear dot-like. PIEZO2 co-localized with cytokeratin 20, chromogranin A, synaptophysin and neurofilament. Moreover, neurofilament immunoreactive structures resembling nerve-Merkel cell contacts were occasionally found. PIEZO2 was also detected in cells of the sweat ducts. The role of PIEZO2 in Merkel cell carcinoma is still unknown, but it could be related with the mechanical regulation of the tumor biology or be a mere vestige of the Merkel cell derivation.

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BACKGROUND: PIEZO2 is a transmembrane protein forming part of an ion channel required for mechanotransduction. In humans, PIEZO2 is present in axon terminals of adult Meissner and Pacinian corpuscles, as well as Merkel cells in Merkel cell-neurite complexes. METHODS: To study the acquisition of functional capability for mechanotransduction of developing type I slowly adapting low-threshold mechanoreceptors, i.e., Merkel cell-neurite complexes, a battery of immunohistochemical and immunofluorescence techniques was performed on human skin specimens covering the whole development and growth, from 11 weeks of estimated gestational age to 20 years of life. In addition, developmental expression of PIEZO2 type I (Meissner's corpuscles) and type II (Pacinian corpuscles) rapidly adapting mechanoreceptors was studied in parallel. RESULTS: The first evidence of Merkel cells showing the typical morphology and placement was at 13 weeks of estimated gestation age, and at this time positive immunoreactivity for PIEZO2 was achieved. PIEZO2 expression in axons terminals started at 23 WEGA in Pacinian corpuscles and at 36 WEGA in the case of Meissner corpuscles. The occurrence of PIEZO2 in Merkel cells, Meissner and Pacinian corpuscles was maintained for all the time investigated. Interestingly PIEZO2 was absent in most Aß type I slowly adapting low-threshold mechanoreceptors that innervate MC while it was regularly present in most Aß type I and type II rapidly adapting low-threshold mechanoreceptors that supplies Meissner and Pacinian corpuscles. CONCLUSION: The present results provide evidence that human cutaneous mechanoreceptors could perform mechanotransduction already during embryonic development.

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We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in-frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well-delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests ('cell balls') was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20-positive Merkel cells were detected. RNA sequencing (RNA-seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT-qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA-seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland.

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Carcinoma de células de Merkel é um tumor neuroendócrino raro e agressivo de pele que usualmente apresenta-se como lesão única na região de cabeça ou pescoço. Relata-se um caso de topografia e apresentação atípicas, com presença de múltiplos e simultâneos tumores na perna esquerda de rápida evolução, associados à linfonodomegalia inguinal palpável, com diagnóstico confirmado por meio de histopatologia e imuno-histoquímica. Realizada exérese de linfonodo inguinal esquerdo e das lesões cutâneas com margem de segurança

Merkel cell carcinoma is a rare and aggressive neuroendocrine skin tumor usually presenting as a single lesion in the head or neck region. We report a case of atypical topography and presentation, with multiple and simultaneous tumors on the left leg of rapid progression associated with palpable inguinal lymphadenopathy and diagnostic confirmation by histopathology and immunohistochemistry. Exeresis of the left inguinal lymph node and skin lesions with a safety margin was performed

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Merkel cell carcinoma (MCC) is a rare neoplasm of unknown multifactorial origin first described in 1972. It occurs most often in older Caucasian males and is typically associated with sun-exposed areas of skin. However, cases have also been reported in other areas, such as the trunk and the gluteal region. Metastatic disease will occur in up to one-third of cases at onset or during the course of the disease, including metastases to the abdominal organs. We present the case of a 53-year-old male with a history of primary MCC of the right buttock and local resection surgery. Eighteen months later, he presented with a small bowel obstruction and had an emergency segmental bowel resection. Pathology examination with immunohistochemistry concluded that findings were consistent with metastatic MCC.

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Pannexins are channel proteins displaying functional similarities to gap junctions in vertebrates and are regarded as transmembrane ATP-releasing channels. A member of this family, denominate pannexin1, has been detected in the epidermis and cutaneous adnexal structures. Here we used immunohistochemistry to investigate whether human digital Merkel cells express this protein since ATP is postulated as a neurotransmitter in the Merkel cell-axon complexes low-threshold mecahoreceptors. Pannexin1 immunoreactivity was found in cytokeratine 20-, chromogranin A- and synaptophysin-positive cells placed at the basal layer of the epidermis. Cell displaying pannexin1 immunoreactivities were thus identified as Merkel cells and showed close contact with nerve profiles. Light pannexin1 immunoreactivity in dermal blood vessels was also verified. Present results demonstrate for the first time the expression of pannexin1 in human digital Merkel cells supporting the idea that ATP can be involved directly or indirectly in the mechanotransductional process at Merkel-axon complexes.

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INTRODUCTION: Skin aging is a natural process that cannot be stopped. However, there are many ways to help attenuate premature aging of the skin and reduce the signs that have already appeared. One of them is the subcutaneous administration of preparations containing a combination of hyaluronic acid, active amino acids, and peptides providing an anti-aging clinical effect. The purpose of this research is to study in vitro new signaling molecules with the anti-aging effects and influence of hyaluronic acid fillers on its expression. METHODS: The study was conducted using cell cultures of human facial skin: 1) mixed culture of human facial skin keratinocytes and fibroblasts, and 2) culture of human facial skin keratinocytes enriched with Merkel cells. Immunocytochemistry, confocal microscopy and Western blot were used to identify markers of aging. RESULTS: HA-Y and HA-S activated the expression of Klotho in the case of aging mixed culture of human skin keratinocytes and Merkel cells. The increase in expression of MTH-1 with aging of cultures provides evidence of activating defense mechanisms against reactive oxygen species that are accumulating with aging, under the action of HA-S and HA-Y. There was a statistically valid increase in the area of expression of melatonin receptor 1A and 1B markers when adding both HA-S and HA-Y to cultured cells. CONCLUSION: This investigation showed that the studied fillers have biological effects, testifying the stimulation of reparative processes in the skin under their control.

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BACKGROUND: Prurigo nodularis (PN) is a highly pruritic disease that significantly impairs patient quality of life. Although the mechanism that causes pruritus is not clear, one hypothesis argues that neural hyperplasia, mast cell, and Merkel cell neurite complexes may be associated with PN pathogenesis. OBJECTIVE: The objective of this study was to analyze whether special staining outcomes differed depending on the presence of atopic dermatitis (AD) and treatment response. METHODS: A total of 209 patients diagnosed with PN was analyzed retrospectively. Patients were divided into two groups according to presence or past history of AD and by treatment response. Histopathologic features were obtained using the following stains: Giemsa, S-100, neuron-specific enolase, cytokeratin (CK)-20, CAM5.2, and CK8/CK18. RESULTS: A total of 126 patients (60.29%) had AD, and 68 (32.54%) showed clinical improvement. There were no statistically significant differences in the staining results between the PN groups with AD (PN c AD) and without AD (PN s AD). Additionally, there were no statistically significant differences in staining results between the improved and non-improved groups. CONCLUSION: Implementing the special stains helped to identify PN pathogenesis. Because there were no statistically significant differences in the special stain results between the improved and non-improved groups, we conclude that mast cell proliferation, neural hyperplasia, and Merkel cell hyperplasia may not have a significant effect on treatment response.

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During embryonic development, hierarchical cascades of transcription factors interact with lineage-specific chromatin structures to control the sequential steps in the differentiation of specialized cell types. While examples of transcription factor cascades have been well documented, the mechanisms underlying developmental changes in accessibility of cell type-specific enhancers remain poorly understood. Here, we show that the transcriptional "master regulator" ATOH1-which is necessary for the differentiation of two distinct mechanoreceptor cell types, hair cells in the inner ear and Merkel cells of the epidermis-is unable to access much of its target enhancer network in the progenitor populations of either cell type when it first appears, imposing a block to further differentiation. This block is overcome by a feed-forward mechanism in which ATOH1 first stimulates expression of POU4F3, which subsequently acts as a pioneer factor to provide access to closed ATOH1 enhancers, allowing hair cell and Merkel cell differentiation to proceed. Our analysis also indicates the presence of both shared and divergent ATOH1/POU4F3-dependent enhancer networks in hair cells and Merkel cells. These cells share a deep developmental lineage relationship, deriving from their common epidermal origin, and suggesting that this feed-forward mechanism preceded the evolutionary divergence of these very different mechanoreceptive cell types.

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Merkel cells are specialized epithelial cells connected to afferent nerve endings responsible for light-touch sensations, formed at specific locations in touch-sensitive regions of the mammalian skin. Although Merkel cells are descendants of the epidermal lineage, little is known about the mechanisms responsible for the development of these unique mechanosensory cells. Recent studies have highlighted that the Polycomb group (PcG) of proteins play a significant role in spatiotemporal regulation of Merkel cell formation. In addition, several of the major signalling pathways involved in skin development have been shown to regulate Merkel cell development as well. Here, we summarize the current understandings of the role of developmental regulators in Merkel cell formation, including the interplay between the epigenetic machinery and key signalling pathways, and the lineage-specific transcription factors involved in the regulation of Merkel cell development.

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Transplantation of embryonic motor neurons has been shown to improve motor neuron survival and innervation of neuromuscular junctions in peripheral nerves. However, there have been no reports regarding transplantation of sensory neurons and innervation of sensory receptors. Therefore, we hypothesized that the transplantation of embryonic sensory neurons may improve sensory neurons in the skin and innervate Merkel cells and Meissner's corpuscles. We obtained sensory neurons from dorsal root ganglia of 14-day rat embryos. We generated a rat model of Wallerian-degeneration by performing sciatic nerve transection and waiting for one week after. Six months after cell transplantation, we performed histological and electrophysiological examinations in naïve control, surgical control, and cell transplantation groups. The number of nerve fibers in the papillary dermis and epidermal-dermal interface was significantly greater in the cell transplantation than in the surgical control group. The percent of Merkel cells with nerve terminals, as well as the average number of Meissner corpuscles with nerve terminals, were higher in the cell transplantation than in the surgical control group, but differences were not significant between the two groups. Moreover, the amplitude and latency of sensory conduction velocity were evoked in rats of the cell transplantation group. We demonstrated that the transplantation of embryonic dorsal root ganglion cells improved sensory nerve fiber number and innervation of Merkel cells and Meissner's corpuscles in peripheral nerves.

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Merkel cell polyomavirus (MCPyV) is a human polyomavirus causally linked to the development of Merkel cell carcinoma (MCC), an aggressive malignancy that largely arises within the dermis of the skin. In this study, we recapitulate the histopathology of human MCC tumors in vitro using an organotypic (raft) culture system that is traditionally used to recapitulate the dermal and epidermal equivalents of skin in three dimensions (3D). In the optimal culture condition, MCPyV+ MCC cells were embedded in collagen between the epidermal equivalent comprising human keratinocytes and a dermal equivalent containing fibroblasts, resulting in MCC-like lesions arising within the dermal equivalent. The presence and organization of MCC cells within these dermal lesions were characterized through biomarker analyses. Interestingly, co-culture of MCPyV+ MCC together with keratinocytes specifically within the epidermal equivalent of the raft did not reproduce human MCC morphology, nor were any keratinocytes necessary for MCC-like lesions to develop in the dermal equivalent. This 3D tissue culture system provides a novel in vitro platform for studying the role of MCPyV T antigens in MCC oncogenesis, identifying additional factors involved in this process, and for screening potential MCPyV+ MCC therapeutic strategies.

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Introdução: O carcinoma de células de Merkel é um raro tumor neuroendócrino cutâneo, que se origina das células responsáveis pela sensibilidade tátil, possui caráter agressivo, evolução rápida e difícil tratamento. Relato do caso: Paciente do sexo masculino, 49 anos, caucasiano, que, ao atendimento dermatológico, apresentou nódulo indolor, infiltrando tecidos profundos, não ulcerado e localizado na região do braço esquerdo. O resultado da biópsia incisional foi positivo para carcinoma de células de Merkel. Após ressecção da lesão, os exames complementares evidenciaram doença metastática na axila e parede torácica. Com o tratamento quimioterápico, houve um benefício inicial com redução tumoral, porém, não durável, uma vez que foram reveladas novas áreas com metástases tumorais em regiões superiores do corpo, sendo submetido a novo procedimento cirúrgico, o qual, após novo regime quimioterápico, não obteve sucesso. Conclusão: Na ocasião do tratamento desse paciente, os anticorpos monoclonais, como o avelumab, não estavam disponíveis. O diagnóstico precoce com cirurgia de exérese da lesão imediata, antes do acometimento de outras regiões, permanece sendo a melhor opção para um prognóstico favorável ao paciente. Contudo, a despeito disso, com as limitações à época do tratamento, o paciente evoluiu a óbito.

Introduction: The Merkel cell carcinoma is a rare cutaneous neuroendocrine tumor that originates from cells responsible for tactile sensitivity, it has an aggressive character, fast evolution and difficult treatment. Case report: 49 years Caucasian male patient, with a painless nodule, infiltrating deep tissue, not ulcerated and located in left arm identified during the dermatological consultation. The result of the incisional biopsy was positive for Merkel cell carcinoma. After resection of the lesion, complementary exams revealed metastatic disease in the axilla and chest wall. The chemotherapy treatment brought an initial improvement with tumor reduction, however, it was not durable, because new areas with tumor metastases in upper regions of the body were revealed, the patient was submitted to an another surgical procedure, after which a new chemotherapy regimen failed. Conclusion:At the time of the treatment of this patient, monoclonal antibodies, such as avelumab, were not available. Early diagnosis with immediate lesion excision surgery, before the involvement of other regions, remains the best option for a better prognosis. However, regardless of this, because of the limitations at the time of the treatment, the patient died.

Introducción: El carcinoma de células de Merkel es un tumor neuroendocrino cutáneo raro, que se origina en células responsables de la sensibilidad táctil, tiene un carácter agresivo, una evolución rápida y un tratamiento difícil. Relato del caso: Paciente masculino, de 49 años, caucásico, que en atención dermatológica encontró nódulo indoloro, infiltrando tejidos profundos, no ulcerados y ubicados en la región del brazo izquierdo. El resultado de la biopsia incisional fue positivo para el carcinoma de células de Merkel. Después de la resección de la lesión, los exámenes complementarios mostraron enfermedad metastásica en la axila y la pared torácica. Con el tratamiento de quimioterapia, hubo un beneficio inicial con la reducción del tumor, sin embargo, no es duradero, ya que se revelaron nuevas áreas con metástasis tumorales en las regiones superiores del cuerpo, que se sometieron a un nuevo procedimiento quirúrgico, que después de un nuevo régimen de quimioterapia no tuvo éxito. Conclusión: En el momento del tratamiento de este paciente, los anticuerpos monoclonales, como avelumab, no estaban disponibles. El diagnóstico temprano con cirugía para la escisión de la lesión inmediata, antes de la participación de otras regiones, sigue siendo la mejor opción para un pronóstico favorable para el paciente. Sin embargo, a pesar de esto, con las limitaciones al momento del tratamiento, el paciente falleció.

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Piezo2 channels are expressed in Merkel cells and somatosensory neurons to mediate mechanotransduction leading to the sense of touch. Components of the cytoskeleton including microtubules are key intracellular structures that maintain cellular membrane mechanics and thereby may be important in mechanotransduction. In the present study, we have explored, with microtubule-targeting agents, the potential role of microtubules in Piezo2-mediated mechanotransduction in Merkel cells of mouse whisker hair follicles. Applying patch-clamp recordings to Merkel cells in situ in whisker hair follicles, we show that Piezo2-mediated mechanically activated (MA) currents in Merkel cells are significantly potentiated by the microtubule stabilizer paclitaxel but reduced by the microtubule destabilizer vincristine. Furthermore, electrophysiological recordings made from whisker hair follicle afferent nerves show that mechanically evoked whisker afferent impulses are significantly enhanced by paclitaxel and its analog docetaxel but significantly suppressed by vincristine and its analog vinblastine. Our findings suggest that microtubules play an essential role in Piezo2 mechanotransduction in Merkel cells.NEW & NOTEWORTHY Piezo2 channels are expressed in Merkel cells to mediate mechanotransduction leading to the sense of touch. Here we determined the role of microtubules in regulating Piezo2-mediated mechanotransduction in Merkel cells. Piezo2-mediated currents in Merkel cells are potentiated by microtubule stabilizer paclitaxel but reduced by microtubule destabilizer vincristine. Mechanically evoked afferent impulses are also enhanced by microtubule stabilizers and suppressed by microtubule destabilizers. Microtubules may play an essential role in Piezo2 mechanotransduction in Merkel cells.

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Molecules present in an animal's environment can indicate the presence of predators, food, or sexual partners and consequently, induce migratory, reproductive, foraging, or escape behaviors. Three sensory systems, the olfactory, gustatory, and solitary chemosensory cell (SCC) systems detect chemical stimuli in vertebrates. While a great deal of research has focused on the olfactory and gustatory system over the years, it is only recently that significant attention has been devoted to the SCC system. The SCCs are microvillous cells that were first discovered on the skin of fish, and later in amphibians, reptiles, and mammals. Lampreys also possess SCCs that are particularly numerous on cutaneous papillae. However, little is known regarding their precise distribution, innervation, and function. Here, we show that sea lampreys (Petromyzon marinus L.) have cutaneous papillae located around the oral disk, nostril, gill pores, and on the dorsal fins and that SCCs are particularly numerous on these papillae. Tract-tracing experiments demonstrated that the oral and nasal papillae are innervated by the trigeminal nerve, the gill pore papillae are innervated by branchial nerves, and the dorsal fin papillae are innervated by spinal nerves. We also characterized the response profile of gill pore papillae to some chemicals and showed that trout-derived chemicals, amino acids, and a bile acid produced potent responses. Together with a companion study (Suntres et al., Journal of Comparative Neurology, this issue), our results provide new insights on the function and evolution of the SCC system in vertebrates.

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