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Merkel cells
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Merkel cells are mechanoreceptors in the basal layer of the epidermis that detect sustained light touch, pressure, and fine surface texture. They are part of the tactile-end organs. They are multimodal epithelial cells localized in the basal epidermal layer. They detect sustained pressure, edges, and fine surface texture, which makes them essential for tasks like reading Braille or identifying an object in the hand. Beyond touch, Merkel cells also contribute to mechanical itch and pain signaling and groups of cells without nerve contact have endocrine and paracrine roles in the skin. Along with their characteristic oval shape, some of the key features of Merkel cells include cytoplasmic processes that extend into and between keratinocytes and the ability to interact via synapse-like structures with nerve endings in the skin.
| Definition |
Type of receptor: Sensory receptor; Type I Mechanoreceptor Stimuli: low threshold Light continuous touch Indentation of the skin Object texture |
| Localization | Epidermis (basal layer) Hairy skin Glabrous skin Mucosal epithelia |
| Morphology |
Typical structure Elliptical shape Superficial spine-like processes Neuroendocrine granules Merkel cell-neurite complex Merkel cell Aβ axon terminals, forming a disc at the base of the Merkel cell (Merkel’s tactile disc) |
| Function |
General characteristics Tonic receptor Slow adaptation (SAI responses) Irregular spiking pattern Mechanotransduction Mechanical stimulus → PIEZO2 opens → cation influx depolarizes the Merkel cell → voltage-gated Ca²⁺ channels open → Ca²⁺-induced Ca²⁺ release → vesicular release of serotonin (and other transmitters) onto the Aβ terminal → SA1 firing in the Aβ fiber Nociception Endocrine and paracrine secretion |
- Where are Merkel cells located?
- Morphology
-
Merkel cell-neurite complex
- Function of Merkel cells
- Merkel cells vs other mechanoreceptors
- Clinical notes
- Sources
Where are Merkel cells located?
Merkel cells are located at the basal layer of the epidermis, along the dermo-epidermal junction (i.e. the interface between the epidermis and the dermis), and accounts for less than 5% of the total cell population of the layer. In touch sensitive areas of hairy skin, they are located around the bulge region of hair follicles, either isolated or in clusters, where -together with keratinocytes and nerve endings- they comprise structures called touch domes. They can also be found in glabrous skin (palms, fingers, feet, and plantar surface of the toes) and some mucosal epithelia (taste buds, palatine ridges, anal canal, and labial epithelium).
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Morphology
Tactile epithelial cells have a distinct elliptical shape, approximately 10 - 15 μm in length. On their surface they have spine-like processes that extend into and between keratinocytes, to which they are attached by small desmosomes. One of the morphological hallmarks of Merkel cells are large, membrane-surrounded neuroendocrine granules: these secretory granules contain specific neuropeptides and biogenic amines, such as vasoactive intestinal polypeptide (VIP), calcitonin gene related peptide (CGRP), substance P, serotonin (5-HT), and norepinephrine (NE). Some of these substances have been shown to promote the proliferation and differentiation of various cutaneous cell types, such as keratinocytes, fibroblasts and endothelial cells.
Tactile epithelial cells, however, exhibit significant heterogeneity, with members of the population presenting differing shapes (from round to oval), length of processes, degrees of innervation and molecular signatures.
Merkel cell-neurite complex
A particularly significant feature of Merkel cells is a contact zone, by which they interact with Aβ (heavily myelinated, rapidly conducting) sensory neurons at the dermo-epidermal junction: this formation is referred to as the Merkel cell-neurite complex (alternatively mentioned in the literature as epithelial tactile complex, Merkel ending, and Merkel’s corpuscle). The contact zone is characterized by a synapse-like cleft, a presynaptic region which is positive for the active-zone protein Piccolo, and a postsynaptic-like density of the nerve terminal’s membrane. These features confirm the presence of synapses between Merkel cells and their associated terminals.
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Epithelial tactile complexes typically consist of 50 - 70 cells, connected by terminals from a single myelinated Aβ afferent fiber. Each axon terminal forms an expanded disc at the base of its target cell, called the tactile meniscus (alternatively Merkel’s tactile disc). Merkel endings -in contrast to other tactile-end organs in the skin such as the Ruffini endings, and the Pacinian and Meissner corpuscles- constitute a unique example of non-encapsulated sensory corpuscles.
Function of Merkel cells
Merkel cells exhibit a vast repertoire of functions, both independently and as part of the epithelial tactile complex. This broad diversity of functions is a testament to the heterogeneity characterizing this particular cell type.
Mechanotransduction
Mechanotransduction is a process during which mechanical stimuli are converted into electrical signals, and finally, into a biological response. The use of optogenetics has allowed for a better understanding of the role of tactile epithelial cells in mechanosensation. Merkel cells mediate mechanotransduction as part of the Merkel cell-neurite complex, by utilizing both mechanosensitive and voltage-activated channels. A characteristic family is PIEZO, whose members (PIEZO 1 and 2) are large, transmembrane proteins, essential for the assembly of non-selective cationic mechanically-gated channels that are permeable by calcium cations. Upon the opening of PIEZO 2 channels, the cellular concentration of calcium rapidly increases, leading to the activation of other, voltage-gated calcium channels. The initial calcium influx further triggers a release of calcium from intracellular stores (calcium-induced calcium release, CICR), thus creating calcium transients and facilitating the prolonged depolarization of the associated Aβ fiber. The utilization of both types of ion channels is the cornerstone of the hallmark electrophysiological characteristics of the epithelial tactile complex, in response to applied mechanical stimuli.
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Merkel cell-neurite complexes act as slowly adapting or tonic, low-threshold mechanoreceptors (LTMRs). In general, tonic receptors adapt in a slow fashion, and are responsible for long lasting responses to various sustained stimuli. These particular receptors are also characterized as low-threshold, meaning that they respond preferentially to innocuous (low intensity) stimuli. Epithelial tactile complexes are also identified as slowly adapting type I units, i.e. mechanoreceptors that detect the velocity of the applied stimulus, and exhibit well-delineated receptive fields, with small, sharp borders. Unlike other mammalian slow-adapting mechanoreceptors, type I units fire in an irregular pattern. The likely cause is chemical synaptic transmission between the Merkel cell and the Aβ terminal. Merkel cell dense-core granules contain serotonin, ATP, and several neuropeptides (CGRP, substance P, VIP, met-enkephalin). Work by Chang and colleagues in mouse whisker hair follicles showed that mechanical stimulation triggers vesicular serotonin release from Merkel cells onto the Aβ-afferent ending, where ionotropic and metabotropic 5-HT receptors generate the SA1 impulse. Merkel cells also express vesicular glutamate transporters, and NMDA receptors are present on the associated afferent, so glutamate signaling contributes alongside serotonin. Hoffman and colleagues have separately reported adrenergic synapses at cutaneous touch domes, indicating that the dominant transmitter may differ between body regions. The mechanically driven calcium rise in Merkel cells supports vesicle release at this synapse-like contact. These traits allow the Merkel cell-neurite complex to distinguish two points in close proximity, consequently indicating the position and speed of various stimuli (e.g. sustained indentation of the skin).
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Nociception
Nociception is the perception of painful (noxious) stimuli, such as chemical and inflammatory factors, extreme temperatures and pressure. PIEZO 2 channels, which –as previously mentioned– are expressed in Merkel cells, are known to detect mechanical stimuli in inflammatory and neuropathic pain. Furthermore, tactile epithelial cells secrete substances, such as calcitonin gene related peptide (CGRP) and substance P, which are consistent in response to irritants, and facilitate the propagation of nociceptive signals.
Endocrine and paracrine secretion
Groups of Merkel cells that are not associated with nerve fibers may have a putative role in endocrine and paracrine secretion, especially during development and homeostasis. This is further supported by data highlighting an increased number of tactile epithelial cells in the bulge region of (adult) hair follicles, which also contain stem cells utilized for hair regrowth. In vitro experiments have shown that some of the neuropeptides contained in Merkel cell secretory granules are able to stimulate cutaneous cell growth and differentiation.
Merkel cells vs other mechanoreceptors
The skin contains four main types of low-threshold mechanoreceptor, each tuned to a different aspect of touch. The table below summarises how the epithelial tactile complex compares with the three encapsulated corpuscles.
| Epithelial tactile complex (Merkel) | Tactile (Meissner) corpuscle | Lamellar (Pacinian) corpuscle | Bulbous (Ruffini) corpuscle | |
| Location | Basal epidermis; touch domes in hairy skin; fingertips and lips | Dermal papillae of glabrous skin (fingertips, palms, soles, lips) | Deep dermis and subcutaneous tissue; also in joints and periosteum | Dermis and subcutis; concentrated near nail beds and joint capsules |
| Encapsulation | Non-encapsulated | Encapsulated | Encapsulated (concentric lamellae) | Encapsulated (thin capsule) |
| Adaptation | Slowly adapting type I (SA1) | Rapidly adapting type I (RA1) | Rapidly adapting type II (RA2) | Slowly adapting type II (SA2) |
| Preferred stimulus | Sustained pressure, edges, fine texture, shape | Light touch, low-frequency vibration (5–50 Hz), skin motion | High-frequency vibration (50–400 Hz), deep pressure | Skin stretch, sustained shear |
| Receptive field | Small, sharp borders | Small, well-defined | Large, diffuse | Large, diffuse |
| Afferent fiber | Aβ (myelinated) | Aβ (myelinated) | Aβ (myelinated) | Aβ (myelinated) |
Take the following quiz and learn the structure and function of Merkel cells as well as the rest of the mechanoreceptors.
Clinical notes
Merkel cell carcinoma
Merkel cell carcinoma (MCC), also known as primary cutaneous neuroendocrine carcinoma, is a rare, highly malignant skin tumor that mainly occurs in elderly and immunosuppressed patients. It usually presents in chronically sun-exposed skin of the head and extremities, though it can also arise in non-sun-exposed sites such as the mucosal surfaces of the mouth, tongue, nasopharynx, and lymph nodes.
MCC has two distinct causes. About 80% of cases are driven by Merkel cell polyomavirus (MCPyV), a ubiquitous virus identified in MCC tumor DNA by Feng and colleagues in 2008. The viral genome integrates into the host DNA and expresses a truncated Large T antigen, which drives tumor growth. The remaining 20% of cases are virus-negative and arise from UV-induced DNA damage; these tumors carry a high mutational burden. Both subtypes behave aggressively, but their molecular profiles differ and increasingly guide treatment decisions.
The cell of origin remains debated. Earlier work proposed non-innervated Merkel cells as the precursor, based on the observation that these tumors rarely arise in locations populated by innervated tactile epithelial cells. More recent evidence points instead to dermal fibroblasts (the cell type MCPyV actively infects) or epidermal stem cells, depending on the subtype.
Clinically, Merkel cell carcinoma usually manifests as a rapidly-growing firm mass, covered by erythematous, pink or bruise-like colored skin. Contrary to other conditions, these tumors tend not to cause pain. The differential diagnosis for this clinical presentation is broad, and it includes conditions such as basal cell carcinoma, squamous cell carcinoma, amelanotic melanoma, cyst, adnexal tumor and lymphoma cutis.
Mechanical allodynia
Mechanical allodynia is a condition according to which innocuous tactile stimuli are interpreted as painful ones. It usually occurs under pathological conditions, such as nerve damage, diabetes and prolonged inflammation. Some instances of allodynia have been observed in patients undergoing chemotherapy. Depending on the type of the triggering stimulus, allodynia is classified in three categories:
Dynamic: innocuous, extremely light tactile stimuli.
Static: pressure.
Punctate: pinch-like triggers.
It is well established that PIEZO 2 channels have a role in pain perception. Experiments in mice have shown that Merkel cell-neurite complexes might also be partially involved in this particular pathology, as a result of peripheral nerve injury. Interestingly, their involvement presents a sex-dependent motif, with male mice lacking epithelial tactile complexes being less susceptible to mechanical allodynia, compared to their wild type counterparts. A similar behavioral paradigm was not observed in female mice.
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