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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.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.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 Aβ type I slowly adapting low-threshold mechanoreceptors that innervate MC while it was regularly present in most Aβ type I and type II rapidly adapting low-threshold mechanoreceptors that supplies Meissner and Pacinian corpuscles.The present results provide evidence that human cutaneous mechanoreceptors could perform mechanotransduction already during embryonic development.

Distal diabetic sensorimotor polyneuropathy (DDSP) is the most prevalent form of diabetic neuropathy, and some of the patients develop gradual pain. Specialized sensory structures present in the skin encode different modalities of somatosensitivity such as temperature, touch, and pain. The cutaneous sensory structures responsible for the qualities of mechanosensitivity (fine touch, vibration) are collectively known as cutaneous mechanoreceptors (Meissner corpuscles, Pacinian corpuscles, and Merkel cell–axonal complexes), which results are altered during diabetes. Here, we used immunohistochemistry to analyze the density, localization within the dermis, arrangement of corpuscular components (axons and Schwann-like cells), and expression of putative mechanoproteins (PIEZO2, ASIC2, and TRPV4) in cutaneous mechanoreceptors of subjects suffering clinically diagnosed non-painful and painful distal diabetic sensorimotor polyneuropathy. The number of Meissner corpuscles, Pacinian corpuscles, and Merkel cells was found to be severely decreased in the non-painful presentation of the disease, and almost disappeared in the painful presentation. Furthermore, there was a marked reduction in the expression of axonal and Schwann-like cell markers (with are characteristics of corpuscular denervation) as well as of all investigated mechanoproteins in the non-painful distal diabetic sensorimotor polyneuropathy, and these were absent in the painful form. Taken together, these alterations might explain, at least partly, the impairment of mechanosensitivity system associated with distal diabetic sensorimotor polyneuropathy. Furthermore, our results support that an increasing severity of DDSP may increase the risk of developing painful neuropathic symptoms. However, why the absence of cutaneous mechanoreceptors is associated with pain remains to be elucidated.

Pacinian corpuscles are onion bulb-like multilayered mechanoreceptors that consist of a complicated structure of axon terminals, Schwann related cells (inner core), endoneural related cells (intermediate layer) and perineurial related cells (outer core-capsule). The cells forming those compartments are continuous and share the properties of that covering the nerve fibers. Small leucine-rich proteoglycans are major proteoglycans of the extracellular matrix and regulate collagen fibrillogenesis, cell signalling pathways and extracellular matrix assembly. Here we used immunohistochemistry to investigate the distribution of class I (biglycan, decorin, asporin, ECM2 and ECMX) and class II (fibromodulin, lumican, prolargin, keratocan and osteoadherin) small leucine-rich proteoglycans in human cutaneous Pacinian corpuscles. The distribution of these compounds was: the inner core express decorin, biglycan, lumican, fibromodulin, osteoadherin; the intermediate layer display immunoreactivity for osteoadherin; the outer core biglycan, decorin, lumican, fibromodulin and osteoadherin; and the capsule contains biglycan, decorin, fibromodulin, and lumican. Asporin, prolargin and keratocan were undetectable. These results complement our knowledge about the distribution of small leucine-rich proteoglycans in human Pacinian corpuscles, and help to understand the composition of the extracellular matrix in these sensory formations.

Producción Científica, The mobility of the primate tongue allows for the manipulation of food, but, in addition, houses both general sensory afferents and special sensory end organs. Taste buds can be found across the tongue, but the ones found within the fungiform papillae on the anterior two thirds of the tongue are the first gustatory structures to come into contact with food, and are critical in making food ingestion decisions. Comparative studies of both the macro and micro anatomy in primates are sparse and incomplete, yet there is evidence that gustatory adaptation exists in several primate taxa. One is the distally feathered tongues observed in non-destructive nectar feeders, such as Eulemur rubriventer. We compare both the macro and micro anatomy of three lemurid species who died of natural causes in captivity. We included the following two non-destructive nectar feeders: Varecia variegata and Eulemur macaco, and the following destructive flower feeder: Lemur catta. Strepsirrhines and tarsiers are unique among primates, because they possess a sublingua, which is an anatomical structure that is located below the tongue. We include a microanatomical description of both the tongue and sublingua, which were accomplished using hematoxylin–eosin and Masson trichrome stains, and scanning electron microscopy. We found differences in the size, shape, and distribution of fungiform papillae, and differences in the morphology of conical papillae surrounding the circumvallate ones in all three species. Most notably, large distinct papillae were present at the tip of the tongue in nectar-feeding species. In addition, histological images of the ventro-apical portion of the tongue displayed that it houses an encapsulated structure, but only in Lemur catta case such structure presents cartilage inside. The presence of an encapsulated structure, coupled with the shared morphological traits associated with the sublingua and the tongue tip in Varecia variegata and Eulemur macaco, point to possible feeding adaptations that facilitate non-destructive flower feeding in these two lemurids., Consejería de Educación y Ciencia (grant number UO-15-INVES-17)

Meissner's corpuscles are the most abundant sensory corpuscles in the glabrous skin of the male prepuce. They are type I, rapidly adapting, low-threshold mechanoreceptors, and their function is linked to the expression of the mechanoprotein piezo-type mechanosensitive ion channel component 2 (PIEZO2). Stimulation of genital Meissner's corpuscles gives rise to sexual sensations. It has been recently demonstrated that digital Meissner's corpuscles, Meissner-like corpuscles, and genital end bulbs have an endoneurium-like capsule surrounding their neuronal elements; that is, the axon and glial lamellar cells, and their axons, display PIEZO2 immunoreactivity. It is unknown whether this is also the case for preputial Meissner's corpuscles. Furthermore, the expression of certain proteins that have been found in Meissner's corpuscles at other anatomical locations, especially in the digits, has not been investigated in preputial Meissner's corpuscles. Here, we used immunohistochemistry to investigate the expression of axonal (neurofilament, neuron-specific enolase), glial (S100 protein, glial fibrillary acidic protein, vimentin), endoneurial (CD34), and perineurial (glucose transporter 1) markers in the preputial and digital Meissner's corpuscles of male participants aged between 5 and 23 years. Furthermore, we investigated the occurrence of the mechanoprotein PIEZO2 in male preputial Meissner's corpuscles. Human male prepuce contains numerous Meissner's corpuscles, which may be grouped or isolated and are regularly distributed in the dermal papillae. Lamellar glial cells display strong expression of S100 protein and vimentin but lack expression of glial fibrillary acidic protein. In addition, they show axonal PIEZO2 expression and have an endoneurial capsule, but no perineurial. Our results indicate that human male preputial Meissner's corpuscles share the immunohistochemical profile of digital Meissner's corpuscles, which is considered to be necessary for mechanotransduction. These data strongly suggest that the structure and function of Meissner's corpuscles are independent of their anatomical location.

Small leucine-rich proteoglycans (SLRPs) regulate different processes and undergo significant alterations in various diseases. Colon carcinomas (CCs) are heterogeneous pathologies with important clinical and molecular differences depending on their location, which makes it interesting to analyze the alterations in SLRPs in right- and left-sided tumors (RS- and LSCCs). SLRP transcription levels were studied in 32 CCs using qPCR compared to healthy colon mucosae samples from the same patients, 20 of them from LSCCs and the remaining 12 from RSCCs. Protein expression of genes with significant differences in their transcriptions was analyzed by immunohistochemistry. The alterations observed were related to survival data. The arrangement of transcription of SLRPs was quite similar in ascending and descending colon, but RS- and LSCCs displayed different patterns of alteration, with a greater number of deregulations occurring in the latter. The analysis of protein expression also indicated changes in the location of these molecules, largely moving to the cell interior. While podocan underexpression showed a trend toward better outcomes, no differences were observed in terms of overall survival. In vitro studies using the HT29 tumor cell line suggest that deregulation of SLRPs could affect cell proliferation. SLRPs constitute new differential markers of RS- and LSCCs, showing differences dependent on the anatomical location of the tumor.

The human palmar aponeurosis is involved in hand proprioception, and it contains different sensory corpuscle morphotypes that serve this role. In palmar fibromatosis (classically referred to as Dupuytren's disease), the palmar aponeurosis undergoes fibrous structural changes that, presumably, also affect the nervous system, causing altered perception. We analysed the various sensory nerve formation morphotypes in the palmar aponeuroses of healthy subjects and patients with palmar fibromatosis. To do this, we used immunohistochemistry for corpuscular constituents and the putative mechanoproteins PIEZO2 and acid-sensing ion channel 2. Free nerve endings and Golgi-Mazzoni, Ruffini, paciniform and Pacinian corpuscles were identified in both the healthy and the pathological conditions. The densities of the free nerve endings and Golgi-Mazzoni corpuscles were slightly increased in the pathological tissues. Furthermore, the Pacinian corpuscles were enlarged and displayed an altered shape. Finally, there was also morphological and immunohistochemical evidence of occasional denervation of the Pacinian corpuscles, although no increase in their number was observed. Both PIEZO2 and acid-sensing ion channel 2 were absent from the altered corpuscles. These results indicate that the human palmar aponeurosis is richly innervated, and the free nerve endings and sensory corpuscles within the palmar aponeurosis undergo quantitative and qualitative changes in patients with palmar fibromatosis, which may explain the sensory alterations occasionally reported for this pathology.

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.

Ruffini's corpuscles are present as long fusiform encapsulated sensory structures in different tissues including the skin. Although physiological analyses strongly suggest their existence in glabrous digital skin, such localisation remains unconfirmed. Here, we have investigated the occurrence of typical Ruffini's corpuscles in 372 sections of human digital skin obtained from 186 subjects of both sexes and different ages (19–92 years). S100 protein, neuron‐specific enolase and neurofilament proteins were detected, and the basic immunohistochemical profile of these corpuscles was analysed. Fewer than 0.3 Ruffini's corpuscles/mm(2) were detected, with density distribution across the fingers being F4 > F3 > F2 > F1 > F5 and absolute values being F2 > F1 > F3 > F4 > F5. Axons displayed neuron‐specific enolase immunoreactivity, glial cells forming the core contained S100 protein, and the capsule was positive for CD34 but not Glut1, demonstrating an endoneurial origin. Present results demonstrate the existence of Ruffini's corpuscles in human glabrous digital skin at very low densities. Moreover, the identified Ruffini's corpuscles share the basic immunohistochemical characteristics of other dermal sensory corpuscles.

The vertebrate skin contains sensory corpuscles that are receptors for different qualities of mechanosensitivity like light brush, touch, pressure, stretch or vibration. These specialized sensory organs are linked anatomically and functionally to mechanosensory neurons, which function as low-threshold mechanoreceptors connected to peripheral skin through Aβ nerve fibers. Furthermore, low-threshold mechanoreceptors associated with Aδ and C nerve fibers have been identified in hairy skin. The process of mechanotransduction requires the conversion of a mechanical stimulus into electrical signals (action potentials) through the activation of mechanosensible ion channels present both in the axon and the periaxonal cells of sensory corpuscles (i.e., Schwann-, endoneurial- and perineurial-related cells). Most of those putative ion channels belong to the degenerin/epithelial sodium channel (especially the family of acid-sensing ion channels), the transient receptor potential channel superfamilies, and the Piezo family. This review updates the current data about the occurrence and distribution of putative mechanosensitive ion channels in cutaneous mechanoreceptors including primary sensory neurons and sensory corpuscles.

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.

Meissner's and Pacinian corpuscles are cutaneous mechanoreceptors responsible for different modalities of touch. The development of these sensory formations in humans is poorly known, especially regarding the acquisition of the typical immunohistochemical profile related to their full functional maturity. Here we used a panel of antibodies (to specifically label the main corpuscular components: axon, Schwann-related cells and endoneurial-perineurial-related cells) to investigate the development of digital Meissner's and Pacinian corpuscles in a representative sample covering from 11 weeks of estimated gestational age (wega) to adulthood. Development of Pacinian corpuscles starts at 13 wega, and it is completed at 4 months of life, although their basic structure and immunohistochemical characteristics are reached at 36 wega. During development, around the axon, a complex network of S100 positive Schwann-related processes is progressively compacted to form the inner core, while the surrounding mesenchyme is organized and forms the outer core and the capsule. Meissner's corpuscles start to develop at 22 wega and complete their typical morphology and immunohistochemical profile at 8 months of life. In developing Meissner's corpuscles, the axons establish complex relationships with the epidermis and are progressively covered by Schwann-like cells until they complete the mature arrangement late in postnatal life. The present results demonstrate an asynchronous development of the Meissner's and Pacini's corpuscles and show that there is not a total correlation between morphological and immunohistochemical maturation. The correlation of the present results with touch-induced cortical activity in developing humans is discussed.

A vulvar case of nevus sebaceus is presented. During the routine histopatological examination, attention was drawn by several corpuscular structures. Immunohistochemistry demonstrated that they were sensory corpuscles, identified respectively as Meissner-like and glomerular corpuscles. Nevertheless, compared with typical Meissner corpuscles from digital glabrous skin, Meissner-like corpuscles identified here were bigger, the axon showed an irregular course, and the lamellar cells were smaller. Regarding the glomerular corpuscles they were bigger but with a normal arrangement of the corpuscular constituents. These findings suggest that these cutaneous sensory corpuscles are part of the nevus sebaceus hamartoma.

The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch‐gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell–neurite complexes, Meissner‐like corpuscles and lanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry to investigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20(+), chromogranin A(+) and synaptophisin(+)) Merkel cells. Most of them were in close contact with Piezo2(−) nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2(+), but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non‐nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low‐threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans.

Meissner corpuscles are cutaneous mechanoreceptors that are usually located in the dermal papillae of human glabrous skin. Structurally, these sensory corpuscles consist of a mechanoreceptive sensory neuron surrounded by non-myelinating lamellar Schwann-like cells. Some authors have described a partially developed fibroblastic capsule of endoneurial or perineurial origin around Meissner corpuscles; however, others have noted that these structures are non-encapsulated. As there is continuity between the periaxonic cells forming the sensory corpuscles and the cells of the nerve trunks, we used immunohistochemistry to examine the expression of endoneurial (CD34 antigen) or perineurial [Glucose transporter 1 (Glut1)] markers in human cutaneous Meissner corpuscles. We also investigated the immunohistochemical patterns of nestin and vimentin (the main intermediate filaments of the cytoskeleton of endoneurial and perineurial cells, respectively) in Meissner corpuscles. The most important finding from this study was that CD34-positive cells formed a partial/complete capsule of endoneurial origin around most Meissner corpuscles, without signs of other perineurial Glut1-positive elements. However, the cytoskeletal proteins of the capsular CD34-positive cells did not include either nestin or vimentin, so the cytoskeletal composition of these cells remains to be established. Finally, the intensity of the immunoreactivity for CD34 in the capsule decreased with ageing, sometimes becoming completely absent in the oldest individuals. In conclusion, we report the first immunohistochemical evidence of the capsule of Meissner corpuscles in humans and demonstrate the endoneurial origin of the capsule.

Decline of tactile sensation associated with ageing depends on modifications in skin and both central and peripheral nervous systems. At present, age-related changes in the periphery of the somatosensory system, particularly concerning the effects on mechanoreceptors, remain unknown. Here we used immunohistochemistry to analyse the age-dependent changes in Meissner's and Pacinian corpuscles as well as in Merkel cell-neurite complexes. Moreover, variations in the neurotrophic TrkB-BDNF system and the mechanoprotein Piezo2 (involved in maintenance of cutaneous mechanoreceptors and light touch, respectively) were evaluated. The number of Meissner's corpuscles and Merkel cells decreased progressively with ageing. Meissner's corpuscles were smaller, rounded in morphology and located deeper in the dermis, and signs of corpuscular denervation were found in the oldest subjects. Pacinian corpuscles generally showed no relevant age-related alterations. Reduced expression of Piezo2 in the axon of Meissner's corpuscles and in Merkel cells was observed in old subjects, as well was a decline in the BDNF-TrkB neurotrophic system. This study demonstrates that cutaneous Meissner's corpuscles and Merkel cell-neurite complexes (and less evidently Pacinian corpuscles) undergo morphological and size changes during the ageing process, as well as a reduction in terms of density. Furthermore, the mechanoprotein Piezo2 and the neurotrophic TrkB-BDNF system are reduced in aged corpuscles. Taken together, these alterations might explain part of the impairment of the somatosensory system associated with ageing.

Nipples represent a highly specialized skin with capital importance in mammals for breastfeeding and additionally in humans due to sexuality. The histological studies regarding this region are scarce, so 42 human nipples were studied to describe the morphology of the nipple innervation. Our results exclude the presence of a rich innervation on nipple's skin or superficial dermis, thus definitely excluding nipple skin from the concept glabrous skin. The presence of mechanoreceptors is limited to scarce Merkel cells on the epidermis and some corpuscular capsulated and non-capsulated structures in the dermis; Merkel cells progressively decrease with ageing. No Meissner corpuscles were found and the rare Pacinian corpuscles identified were close to vascular structures and embroidered in the mammary fatty tissue. The great sensitivity observed functionally on the breast and especially in the nipple can be morphologically explained by two elements; on the one hand there is a rich smooth muscle innervation present in the deep dermis; on the other hand the mammary gland demonstrate Piezo2 expression in many glandular cells, with two differentiated patterns in the ductal and in the acinar tissue of the breast. The role of Piezo2 in the normal mammary gland is discussed.

Chondroitin sulfate is a glycosaminoglycan involved in maintaining the morphofunctional properties of the extracellular matrix in peripheral nerves, but its distribution in human sensory corpuscles is unknown despite the role of extracellular matrix in mechanotransduction and axonal guidance. In this study we used immunohistochemistry to analyze the distribution of chondroitin sulfate in human cutaneous Meissner and Pacinian corpuscles. Chondroitin sulfate expression was absent from Meissner corpuscles. In Pacinian corpuscles chondroitin sulfate was found associated to a CD34 positive endoneurial-related layer, interposed between the S100 protein positive inner core cells, and the vimentin positive inner core and outer core-capsule cells. Therefore, the intermediate CD34+/chondroitin sulfate+ intermediate layer present in Pacinian corpuscles isolates the neural segment of the corpuscles (axon and inner core) from the non-neural segments (outer core and capsule). These results suggest a role of chondroitin sulfate in the proper axonal growth and guidance, within the neuronal compartment of the Pacinian corpuscles during development and reinnervation, can be hypothesized. Moreover, a role of CS in mechanotransduction cannot be ruled out. Anat Rec, 302:325-331, 2019. © 2018 Wiley Periodicals, Inc.