Merkel cells: A collective review of current concepts

“com cells that are devoid of contact to nerve terminals also came to be known by the same term.[5,7,8]”

“[27] Several dense core vesicles of about 50–110 nm are concentrated near the juncture with the nerve ending.[28] The MCs in apposition with the afferent sensory nerve endings is also referred to as Merkel’s corpuscle/MC‐neurite complex/Merkel ending.”

“[42] Although it is hard to differentiate between the nervous and endocrine actions of MCs, it is recognized that they can perform both functions namely synthesis and storage of local hormones and neurotransmitters.[43]”

“MC hyperplasia along with keratinocyte hyperproliferation is a frequent histological finding in adnexal tumors namely trichoblastomas, sebaceous nevus, and hidradenomas.[2,58] The increased cell number is often encountered with hyperplasia of nerve terminals that exist in neurilemmoma, neurofibroma, prurigo nodularis,…”

“[11] MCs are also discerned in the male prepuce, clitoris, and esophagus.[12,13] MCs are more distributed in the skin exposed to sun than in concealed skin.”

“[2] Their differentiation from the pleuripotent cells is governed by the essential transcription factor Atoh1 (Factor atonal hemolog 1).[24]”

“[26] The axon terminal (tactile meniscus) contains mitochondria and clear vesicles.[29] A single primary afferent type I nerve fiber innervates the complex.”

“[7] Gottschaldt and Vahle‐Hinz pointed out that the number of synapses is insufficient so as to generate action potential and hence it was the nerve endings themselves that functioned as transducers and not the MCs.[47] Positive immunohistochemical expression of anti‐villin and Epsin antibodies in the micro villis of…”

“[9] However, cells of taste buds and various epithelia of the gastrointestinal tract also show CK20 positivity.[34,35]”

“[17] Various hypotheses are proposed concerning the development of MCs.”

“MCs are distributed in both skin and mucosal tissues, the density of which is increasingly noted in the palms, finger pads, feet, and plantar surface of the toes.[9,10] They are comparatively more in the oral mucosa.”

“(2015) concluded that conduction of mechanical stimuli through Piezo 2 ion channels is fundamental for slowly adapting type 1 responses in cutaneous sensory nerve fibers.[50] García‐Mesa et al.”

“[30] The cells have a distinctive intranuclear rodlet and vesicles.[18] Sometimes, MCs contain melanosomes that are taken from the melanocytes similar to keratinocytes[31] [Figure 2].”

“[2] The origin is still debated that whether they differentiate from epidermal keratinocyte‐like cells or emerge from the migrated stem cells of neural crest origin.[2,3] The functions have been uncertain, but they seem to be involved in neural development and tactile sensation.”

“Despite several neurosensitive components being identified by immunohistochemistry, the exact neurotransmitter in the Merkel’s corpuscle could not be elucidated.[32] Since the oral mucosa, both in normalcy and pathology, displays numerous noninnervated MCs with secretory phenomena, it suggests that MCs have diverse su…”

“[12,13] MCs are more distributed in the skin exposed to sun than in concealed skin.[14] Histologically, they appear clear and oval, localized in the basal cell layer of the epidermis.”

“Since the discovery, the origin of MCs has remained controversial.[17] Various hypotheses are proposed concerning the development of MCs.”

“It is presumed that they play a crucial role in the development of hair follicles and eccrine sweat glands.[37] Merkel’s corpuscles may discharge endocrine constituents via autonomic neural regulation.”

“[7] The granules within the MCs are marked positive for opioid growth factor, calcitonin gene‐related peptide (CGRP), somatostatin, pancreastatin, bombesin, vasoactive intestinal polypeptide (VIP), serotonin, Substance P (SP), glutamate, adenosine triphosphate, and enkephalin.[7,36]”

“Immunoreactivity for CK20 by both SCCs and MCs shows that they are correlated.[40]”

“[47] Positive immunohistochemical expression of anti‐villin and Epsin antibodies in the micro villis of MCs validates the transduction property.[48,49] Researches by Woo et al.”

“MCs degenerate and are significantly reduced in number after denervation, but they never disappear completely.[56] They continue to survive in transplanted cutaneous flaps and their sustenance is strongly correlated with the recovery of the tactile sensation.”

“The somatosensory function of the MCs of palatine ridges is supported by the transduction through release of glutamate.[45] An increase in intracellular calcium concentration within the cells is recorded during mechanical stimulation.”

“MC hyperplasia along with keratinocyte hyperproliferation is a frequent histological finding in adnexal tumors namely trichoblastomas, sebaceous nevus, and hidradenomas.[2,58] The increased cell number is often encountered with hyperplasia of nerve terminals that exist in neurilemmoma, neurofibroma, prurigo nodularis,…”

“In the epidermis developed from the embryos that were deprived of neural precursors, Tweedle identified MCs.[20] Moll et al.”

“[18] Intermediate filaments are discerned that may sometimes form tonofibril‐like aggregates around the nucleus and neurofilaments.[26] Various zones of specialized synapses appose cytoplasmic membrane with axonal terminal.”

“concluded from their researches on chimeric/avians that MCs originate from neural components.[2,19]”

“It is still ambiguous whether the cellular origin is from epidermal elements or NCCs.”

“[32] Since the oral mucosa, both in normalcy and pathology, displays numerous noninnervated MCs with secretory phenomena, it suggests that MCs have diverse subsets of cells with distinctive actions.[33]”

“[40,41] In the development of the subepidermal nerve plexus in the embryo, MCs are suggested to be involved.[42] Although it is hard to differentiate between the nervous and endocrine actions of MCs, it is recognized that they can perform both functions namely synthesis and storage of local hormones and neurotransmitt…”

“attributed the immunoreactivity to Peizo 2 to very fine and selective tactile perception but not to hard touch and vibration in afferent fibers.[44]”

“[9,10] They are comparatively more in the oral mucosa.[11] MCs are also discerned in the male prepuce, clitoris, and esophagus.”

“[2] Junctions between terminal axons and MCs are formed by adherens junctions/intermediate junctions/belt desmosomes.[30] The cells have a distinctive intranuclear rodlet and vesicles.”

“”[1] He considered them as conductors of physical stimuli as they were proximate to intraepidermal neurites.”

“According to the ultrastructural studies, distinct groups of MCs are identified at diverse locations in the body.[16]”

“[26] Various zones of specialized synapses appose cytoplasmic membrane with axonal terminal.[27] Several dense core vesicles of about 50–110 nm are concentrated near the juncture with the nerve ending.”

“The population increase exponentially in the subsequent weeks.[22,23] Since MCs are recognizable and transplantable several weeks before other NCC derivatives reach the fetal epidermis, it was proposed that MCs do not originate from NCCs.”

“MCs have a striking resemblance to the endocrine‐paracrine (APUD) cells of the epithelium of the genitourinary tract and bronchial mucosa.[7,10,54] Adjacent to the MCs, in the basal layer of the epidermis and in the mucosa of ectodermal origin, pale ovoid cells with dense core granules with multiple nuclear pores on t…”

“In a single cell profile, the granules are adjacent to the Golgi complex in the apical surface rather than the basal surface.[7,55]”

“[9] However, cells of taste buds and various epithelia of the gastrointestinal tract also show CK20 positivity.[34,35]”

“[47] Positive immunohistochemical expression of anti‐villin and Epsin antibodies in the micro villis of MCs validates the transduction property.[48,49] Researches by Woo et al.”

“[45] An increase in intracellular calcium concentration within the cells is recorded during mechanical stimulation.[46] Mechanical transduction function is validated by various electrophysiological data.”

“The cells require ultrastructural methods for their identification as they are difficult to be observed in light microscopy.[4,5] This article provides a review on the current thinking, distribution, origin, function, demonstration, and fate of the human MCs.”

“CGRP and SP released from Merkel’s corpuscles are the active mediators for transferring nociceptive signals and are consistent in reaction to irritating substances.[51]”

“Solitary chemoreceptor cells (SCCs) are the specialized chemosensory cells in the olfactory epithelium that synapses with trigeminal afferent nerve fibers.[52] Functional studies indicate that they can detect inhaled noxious substances.”

“A coexistence of MCs with Langerhans cells inside the bulge area of hair follicles is considered to be a putative reservoir of hair follicle stem cell.[38] Misery developed “Neuroimmunocutaneous system” concept where abundant cellular interactions occur amidst nerve fibers, immune cells, and epithelial cells permit mo…”

“[9] They intertwine with the surrounding keratinocytes by comparatively small, few desmosomes.[25] The nucleus is large, pale, and lobulated with few nucleoli.”

“[18] Sometimes, MCs contain melanosomes that are taken from the melanocytes similar to keratinocytes[31] [Figure 2].”

“[56] They continue to survive in transplanted cutaneous flaps and their sustenance is strongly correlated with the recovery of the tactile sensation.[57]”

“Merkel cell, a functional cell of the sensory systems, and melanocytes are found in this layer [31, 32].”

“Apart from that, Langerhan’s cells, which are involved in the immune response and Merkel cells that are responsible for light touch sensation, can also be found within this layer [62,63].”

“Merkel cells are located in or near the basal layer ac as sensory recept rs in h skin [25].”

“The latter complies with the role of touch sensors [60].”

“This biomechanical adaptation enhances the ability to detect incipient slip and evaluate frictional properties, facilitating rapid feedback for grip adjustment ( 37 ).”

“…nerve fibers and specialized receptors, subserving proprioceptive (joint, muscle, connective tissue) and cutaneous sensitivity, are activated during the execution of FST (for overview of physiological fundamentals of touch see (Abraham and Mathew, 2019; Grunwald, 2008; McGlone and Reilly, 2010).”

“Strikingly, robust EGFP and CB2 expression was detected onMerkel cells in the SB of the epidermis where they produce neuromodulatory effects on lowthreshold mechanoreceptive Merkel endings supplied by myelinated Ab DRG neurons that might contribute to mechanical allodynia under pathological conditions.(1,30)”

“The second type of dendritic cells is the Merkel cells, which act as transducers for fine touch (Abraham and Mathew 2019).”

“Additionally, the basal layer hosts stem cells, allowing skin homeostasis, and serves as the anchorage site for migrating melanocytes and Merkel cells [8–10].”

“Additionally, Merkel cells secrete the CD200 protein, which holds significance in the inflammatory process [25].”

“They are essential for neuroendocrine functions, and due to their synapse-like contacts with neurons, these cells are instrumental for sensing pain and mechanical stimuli such as light touch and hypotoniainduced cell swelling (Abraham and Mathew, 2019).”

“It is hypothesized that these cells play a role in sensory discernment and are in contact with afferent sensory endings [25].”

“Melanocytes produce the pigment melanin for photoprotection [30], and Merkel cells help skin to sense tactile stimuli [31].”

“Merkel cells are specialized cells that exhibit a neuroendocrine function due to their closeness to nerve endings, as they receive the sensation of touch, producing substances that act as hormones [43].”

“Merkel cells are considered to be a type of neuroendocrine cell that forms a cellular axonal complex with sensory nerve fibers [74,75], enabling the perception of pain.”

“However, it should be noted that standard hand washing practice is preferable and more effective if the hands are visibly dirty, greasy or contaminated as the hand surface coverage when alcohol based hand sanitizers are used stands at 20-30seconds hence the coverage is limited [50,51].”

“Alternatively, it may be that sustained changes in tonic firing of rates of slow adapting mechanoreceptors (for review, see Knibestol, 1975; Abraham and Mathew, 2019) in response to the strong pressure manipulation (right hand), result in a distinct tactile representation in left S1 during CS (cid”

“Although MCC was initially thought to arise from neuroendocrine skin epidermal cells responsible for hair follicle regulation and mechanical transduction [10,11], numerous distinctions between MCC and Mer-kel cells suggest that this may be a historic misnomer.”

“To test if human epidermal MCs express OR2AT4 protein, we performed double-immunofluorescence staining for canonical MC markers, the keratins K20, K18 and K8, 1,15,30– 33 alongside with OR2AT4, using freshly embedded healthy human skin.”

“Functionally, Merkel cells are slow-adapting mechanoreceptors that transduce light touch but have been found to have other roles in the endocrine and immune systems [5].”

“(for review, see Knibestol, 1975; Abraham and Mathew, 2019) in response to the strong pressure manipulation (right hand) result in a tactile representation state in left S1 during CS- trials”

“However, it should be noted that standard hand washing practice is preferable and more effective if the hands are visibly dirty, greasy or contaminated as the hand surface coverage when alcohol based hand sanitizers are used stands at 20-30seconds hence the coverage is limited [51].”

“…receptors (SCC and EC) establish specialized direct connections with the central nervous system (CNS) via nerves, including the olfactory (OBG), tri-geminal (SCC), glossopharyngeal (TB and CB), and vagus nerves (TB, NEB, SCC, and EC) (Abraham and Mathew, 2019; Caretta and Mucignat-Caretta, 2022).”