Merkel Cell

Merkel cells, also known as Merkel-Ranvier cells or tactile epithelial cells, are oval-shaped mechanoreceptors present in vertebrate skin that are important for light touch feeling. They are plentiful in extremely sensitive skin, such as the skin of the human fingers, and create synaptic connections with somatosensory afferent nerve fibres.

What exactly is a merkel cell?

Merkel cells are post-mitotic cells found throughout vertebrate epidermis. They are especially fascinating because to the intimate interactions they form with sensory nerve terminals and the large variety of peptides they may produce.

These characteristics imply that they may play a key role in skin homeostasis and cutaneous nerve growth. These cells, however, remain a mystery since they are difficult to analyse. They have not been effectively cultivated and cannot be isolated, making molecular biology and functional research very difficult.

Structure of Merkel Cell

Merkel cells are present in all vertebrates’ skin and certain areas of their mucosa. They are transparent cells around 10 m in diameter found in the stratum basale (at the bottom of sweat duct ridges) of the epidermis of mammals.

They may also be found in rete ridges, which are epidermal invaginations of the plantar foot surface. They are most often connected with sensory nerve ends, in which case they are referred to as Merkel nerve endings (also called a Merkel cell-neurite complex).

Slowly adapting (SA1) somatosensory nerve fibres are connected with them. Low vibrations (5–15 Hz) and deep static contact, such as forms and edges, elicit a response.

Because of their narrow receptive field (very specific information), they are most often utilised in locations such as the fingers; they are not covered (shelled) and hence react to pressures over lengthy periods of time.

History of Merkel Cell

History of Merkel Cell

For more than two decades, scientists have questioned the origins of Merkel cells. Skin graft research in birds suggest that they are generated from the neural crest, whereas experiments in mammals now show that they are produced from the epidermis.

The Anatomical Distribution

MCs are found in both skin and mucosal tissues, with a higher density in the palms, finger pads, foot, and plantar surface of the toes. They are more prevalent in the oral mucosa. Male prepuce, and oesophagus are also found to have MCs. MCs are more prevalent in sun-exposed skin than in hidden skin. Histologically, they seem clear and oval, and are located in the epidermis’ basal cell layer.

Microscopy

  • The morphologic description is mostly accomplished via the use of electron microscopy. The cell is ovoid/elliptical in shape and is 10–15 m in length. They are found in clusters in the stratum basale, near to nerve ends.

  • The surface features up to 50 spine- or microvilli-like projections that may reach up to 2.5 m in length. They are linked to the surrounding keratinocytes via a modest number of desmosomes. The nucleus is big, pale, lobulated, and has few nucleoli.

  • The electron-dense granules in the cytoplasm, which are around 80–100 nm in diameter, are bordered by thin electron-lucent areas and are delimited by simple membranes. They are located distant from the Golgi apparatus and are concentrated in cytoplasmic regions near to nerve terminations.

  • There are intermediate filaments that may form tonofibril-like aggregates surrounding the nucleus and neurofilaments. Various zones of specialised synapses attach to the cytoplasmic membrane and terminate at the axonal terminal. Several dense core vesicles of around 50–110 nm are localised near the nerve terminal junction.

  • Merkel’s corpuscle/MC-neurite complex/Merkel ending refers to the MCs in apposition with the afferent sensory nerve ends. Mitochondria and transparent vesicles are seen at the axon terminal (tactile meniscus).

  • The complex is innervated by a single main afferent type I nerve fibre. Adherens junctions/intermediate junctions/belt desmosomes establish connections between terminal axons and MCs.

  • The cells are distinguished by an intranuclear rodlet and vesicles. Melanosomes, which are extracted from melanocytes in the same way as keratinocytes are, are sometimes seen in MCs.

  • MCs are found in the upper infundibulum of hair follicles, either in the bulge region or near the skin surface. According to ultrastructural research, separate groupings of MCs have been found at various sites throughout the body.

  • MCs exhibit both epithelial and neuroendocrine markers in immunohistochemistry. Low-molecular-weight cytokeratins such as CK8, CK18, CK19, and CK20 stain favourably for intermediate filaments. In normal skin, CK20 is an active marker for those MCs. Cells of taste buds and other epithelia of the gastrointestinal system, on the other hand, are CK20 positive.

  • There is evidence of neuroendocrine immunohistochemical adjuncts such as chromogranin A, protein gene product 9.5, neuron-specific enolase, and synaptophysin.

  • Opioid growth factor, calcitonin gene-related peptide (CGRP), somatostatin, pancreastatin, bombesin, vasoactive intestinal polypeptide (VIP), serotonin, Substance P(SP), glutamate, adenosine triphosphate, and enkephalin are all found in the granules of the MCs.

Summary

This review offers a fresh perspective on the skin’s least-known cells. The many peptides they generate and release may enable them to connect with cells other than neurons, and Merkel cells may play an important role in skin physiology and physiopathology.

Functions

The German anatomist Friedrich Sigmund Merkel referred to these cells as Tastzellen, or “touch cells,” although their supposed function has been contentious due to the difficulty in proving it.

However, genetic knockout mice have recently shown that Merkel cells are required for the specific coding that afferent neurons use to determine precise spatial details.

APUD cells (an older concept) are occasionally used to describe Merkel cells. Because they include dense core granules and hence may have a neuroendocrine function, they are more usually classed as a member of the scattered neuroendocrine system.

:small_blue_diamond: Nervous and endocrine function

The MC granules’ endocrine function is related to the fact that they have remarkable similarities to the dense-core granules of the amine precursor uptake and decarboxylation (APUD) system. Progenitor cells for hair growth and regeneration are found in MCs found in terminal hair follicles. They are thought to be important in the formation of hair follicles and eccrine sweat glands.

:small_blue_diamond: The function of mechano-transduction

Mechanotransduction is the process by which mechanical energy is converted into electrical impulses in the peripheral nervous system.

According to recent findings, MCs act as mechanical transducers, generating impulses in nerve terminals through ionotropic receptors/ligand-gated ion channels. The somatosensory function of the MCs of the palatine ridges is maintained by glutamate transduction.

Mechanical stimulation causes an increase in intracellular calcium concentration inside the cells. Various electrophysiological results confirm the mechanical transduction function.

Gottschaldt and Vahle-Hinz pointed out that the number of synapses is inadequate to create action potentials, hence the nerve terminals themselves served as transducers rather than the MCs.

:small_blue_diamond: The nociception function

The active mediators for conveying nociceptive signals, CGRP and SP released by Merkel’s corpuscles, are constant in response to irritating chemicals.

Solitary chemoreceptor cells (SCCs) are specialised chemosensory cells found in the olfactory epithelium that connect to trigeminal afferent nerve fibres. Functional investigations show that they can detect hazardous chemicals breathed. Both SCCs and MCs have CK20 immunoreactivity, indicating that they are linked.

:small_blue_diamond: Functions that are assumed

Though not universally recognised, the following responsibilities are recommended as a starting point for future study. Because MCs are numerous inside the epidermal ridges of nonhairy skin, they may play a role in fingerprint pattern formation.

MCs with efferent neural signalling capabilities may be able to produce electromagnetic fields for telekinesis. Because of their varied distribution and neurocutaneous signalling, MCs may be able to transduce environmental cues to oocytes, hence altering epigenetic imprinting.

Merkel Cellular-Like Cells

MCs exhibit a remarkable similarity to endocrine-paracrine (APUD) cells of the genitourinary tract epithelium and bronchial mucosa. Pale ovoid cells with dense core granules and many nuclear pores on the oval nuclei are discovered next to the MCs in the basal layer of the epidermis and in the mucosa of ectodermal origin.

These cells have no interaction with nerve terminals, few intercellular connections, and no cytoplasmic structures. In a single cell profile, the granules are located on the apical surface, rather than the basal surface, of the Golgi complex.

Skin Lesions and Merkel Cells

Serum autoantibodies against MCs have been reported in patients with graft-versus-host disease and pemphigus vulgaris. MCs are undetectable in lesional skin of active vitiligo, indicating that they are involved in neurological or autoimmune damage.

MC hyperplasia in conjunction with keratinocyte hyperproliferation is a common histological feature in adnexal tumours such as trichoblastomas, sebaceous nevi, and hidradenomas.

Increased cell number is often associated with nerve terminal hyperplasia in neurilemmoma, neurofibroma, prurigo nodularis, and lichen simplex chronicus.

MC carcinoma is an extremely uncommon, fast developing, cutaneous neuroendocrine tumour that occurs in the head and neck area and has a proclivity to recur and metastasis. It is thought to be generated from MCs due to histopathological similarities.

Summary

Autonomic neuronal control may allow Merkel’s corpuscles to release endocrine components. The cohabitation of MCs and Langerhans cells within hair follicle bulges is thought to constitute a potential reservoir of hair follicle stem cells.

Clinical research publications

Clinical research of merkel cell

The clinical papers and scientific studies listed below give further in-depth information regarding Merkel cells.

Light-touch reactions need Merkel cells.

Although Friedrich Merkel felt that the direct linkage of these cells to nerves indicated that they were ‘touch cells,’ science had to wait almost 120 years to confirm this. Normal cutaneous sensibility was lost in mice whose normal Merkel cells were destroyed in studies.

What are the cells that cause Merkel cell carcinoma?

  • Merkel cell carcinoma (MCC), a very aggressive skin tumour that is becoming more common, has been linked to the recently found Merkel cell polyomavirus (MCPyV).

  • Although research on MCC and MCPyV, as well as other risk factors, has greatly enhanced our understanding of MCC pathophysiology, the cells of origin, which might be critical targets in future treatments, remain unclear. Because of their phenotypic similarities,

  • Merkel cells (MCs), the neuroendocrine cells of the skin, were thought to be the origin of MCC.

  • However, for a variety of reasons, including uneven differentiation of MCCs and the postmitotic nature of MCs, it seems unlikely that MCCs emerge from differentiated MCs.

  • Skin stem cells, most likely of the epidermal lineage, are more likely to be the genesis of MCC. Future research will need to address these problems more closely in order to identify the physiological cells that change into MCC cells.

Merkel cells are derived from epidermal progenitors.

Merkel cells (MCs) are found in the touch-sensitive epidermis and are responsible for mechanotransduction in the skin. Since their discovery more than 130 years ago, whether MCs are derived from embryonic epidermal or neural crest progenitors has been a source of heated debate.

Furthermore, it is yet uncertain how MCs are maintained into maturity. Using lineage-tracing studies, we demonstrate that MCs form throughout embryonic development via the differentiation of epidermal progenitors.

Adult MCs have a delayed turnover and are replaced by cells derived from epidermal stem cells rather than by differentiated MC proliferation. The lack of MCs in all body sites, including the whisker area, is caused by conditional deletion of the Atoh1/Math1 transcription factor in epidermal progenitors.

Our findings show that MCs form from the epidermis through an Atoh1-dependent pathway, opening up new paths for research into MC roles in sensory perception, neuroendocrine signalling, and MC cancer.

The epidermal lineage gives rise to mammalian Merkel cells.

Merkel cells are skin specialised cells that are required for appropriate brain encoding of light touch impulses. According to conflicting data, these cells are derived from either the skin or the neural crest.

To answer this issue, we employed epidermal (Krt14(Cre)) and neural crest (Wnt1(Cre)) Cre-driver lines to precisely remove Atoh1 from the skin and neural crest lineages of mice.

Deletion of Atoh1 from the skin lineage resulted in the loss of Merkel cells across the skin, but deletion from the neural crest lineage had no impact on this cell type. As a result, mammalian Merkel cells are descended from the skin lineage.

What exactly is a Merkel cell cancer (MCC)?

MCC is a rare kind of skin cancer. It starts in the epidermis, the skin’s top layer, near nerve endings. MCC generally moves swiftly. If it metastasizes (spreads) beyond the skin, it might be difficult to cure.

MCC manifests as a discoloured bulge or lump on a sun-exposed patch of skin. It is also known as trabecular carcinoma or neuroendocrine skin cancer.

Who is at risk of developing Merkel cell carcinoma (MCC)?

MCC may be created by anybody. You are more likely to acquire this kind of cancer if you:

  • Have lighter skin tone

  • Spend a significant amount of time outside in direct sunshine.

  • Are above the age of 50

  • Are men

  • Have a compromised immune system

  • Psoriasis may be treated using tanning beds or UV light treatment.

  • Have another sort of cancer, particularly a skin cancer

MCC affects around 0.6 per 100,000 persons in the United States each year. This has increased around fourfold since 1986. However, it should be highlighted that diagnosis has improved, the population is ageing, and the use of immunosuppressant drugs is increasing.

It is estimated that around 700 persons with MCC die each year. One out of every three people dies. Melanoma, another severe disease, is reported to kill one out of every nine individuals each year.

Diagnosis

The following tests and techniques are used to diagnose Merkel cell carcinoma:

  • Physical examination. Your doctor will look for atypical moles, freckles, pigmented areas, and other growths on your skin.

  • Taking a sample of suspect skin. A skin biopsy is a technique in which your doctor removes the tumour or a sample of the tumour from your skin. In a laboratory, the sample is examined for symptoms of malignancy.

Total Number of Patients Surveyed = 1034
Median Age of Patient (years) 74
Age groups (years) No. (%)
< 65 247 (23.9)
65-74 281 (27.2)
>/= 75 506 (48.9)
Race No. (%)
White 968 (93.6)
Black 12 (1.2)
Other 37 (3.6)
Unknown 17 (1.6)
Body site No. (%)
Head 499 (48.3)
Trunk 117 (11.3)
Upper limb 199 (19.3)
Lower limb 165 (16.0)
Other 54 (5.2)
Stage at diagnosis No. (%)
Localized 507 (49.0)
Regional 281 (27.2)
Distant 81 (7.8)
Unknown 165 (16.0)

Determining the scope

Your doctor may order the following tests to see whether the cancer has spread beyond your skin:

:black_small_square: Biopsy of a sentinel node. A sentinel node biopsy is a test to see whether cancer has spread to your lymph nodes. A dye is injected near the malignancy during this treatment. The dye then travels to your lymph nodes through the lymphatic system.

:black_small_square: The sentinel nodes are the first lymph nodes to receive the dye. Your doctor will remove these lymph nodes and examine them under a microscope for malignant cells.

:black_small_square: Imaging examinations. A chest X-ray and a CT scan of your chest and abdomen may be recommended by your doctor to assess if the cancer has spread to other organs.

Other imaging procedures, such as a positron emission tomography (PET) scan or an octreotide scan — a test that utilises an injection of a radioactive tracer to screen for the spread of cancer cells — may also be considered by your doctor.

Treatment of Merkel Cell Carcinoma

Merkel cell carcinoma treatment options include:

:small_blue_diamond: Surgery

During surgery, your doctor will remove the tumour as well as a border of normal skin around it. If there is indication that the cancer has progressed to lymph nodes around the skin tumour, those nodes are removed (lymph node dissection).

To remove the cancer, the surgeon usually uses a knife. In certain situations, your doctor may perform a treatment known as Mohs surgery.

Thin layers of tissue are removed carefully during Mohs surgery and examined under a microscope to see if they contain cancer cells. If cancer is discovered, the surgical procedure is repeated until no cancer cells are visible in the tissue. This form of surgery removes less normal tissue, resulting in less scarring, but it also assures a tumor-free skin border.

:small_blue_diamond: Radiation Treatment

Radiation treatment includes irradiating cancer cells with high-energy beams such as X-rays and protons. You are positioned on a table during radiation therapy, and a big machine travels around you, guiding the beams to specific locations on your body.

After surgery, radiation treatment is occasionally used to eliminate any cancer cells that remain after the tumour has been removed.

Radiation therapy may also be utilised as the only treatment in patients who do not choose to undergo surgery. Radiation may also be used to treat cancer that has spread to other parts of the body.

:small_blue_diamond: Immunotherapy

Drugs are used in immunotherapy to assist your immune system in fighting cancer. Immunotherapy is most often used to treat Merkel cell carcinoma that has progressed to other parts of your body.

:small_blue_diamond: Chemotherapy

Chemotherapy is the use of chemicals to destroy cancer cells. Chemotherapy medications may be given to you via a vein in your arm, as a tablet, or both.

Chemotherapy is seldom used, but it may be recommended if your Merkel cell carcinoma has progressed to your lymph nodes or other organs, or if it has returned after treatment.

Staging of Merkel Cell Carcinoma

The process of determining whether cancer has spread to other places of the body is known as staging. It is critical to understand the stage of the illness in order to determine the optimal therapy.

Following the diagnosis of Merkel cell carcinoma, more tests will be performed to determine if cancer cells have migrated from the site of origin to other regions of the body.

Merkel cell carcinoma is classified into the following stages:

:black_small_square: Stage 1: The main tumour dimension is less than or equal to 2 cm with no lymph node involvement.

:black_small_square: Stage 2: The main tumour has a maximal diameter of more than 2 cm but no lymph nodes are involved.

:black_small_square: Stage 3: Regional lymph nodes are impacted or there is an in-transit metastasis in Stage III.

:black_small_square: Stage 4: The tumour has spread to any distant place other than the region’s lymph nodes and/or internal organ (visceral) involvement.

Merkel Cell Carcinoma Prevention

Other than reducing one’s risk factors, there are no proven ways for preventing MCC. Excessive prolonged sun exposure is typically suggested in the prevention of a range of skin malignancies throughout one’s life.

Summary

Merkel cells are thought to originate in the neural crest of avians and mammals, and their “random” emergence in the epidermis may be the result of a neuron-independent epidermal differentiation process.

Frequently Asked Questions

People usually asked mant quentions about Markel Cell. A few of them are discussed below:

1. Is it possible to treat Merkel cell cancer?

Merkel cell carcinoma is largely curable, both surgically and nonsurgically, if detected early. Treatments are often extremely personalised, based on a patient’s overall health as well as the location, size, depth, and degree of dissemination of the tumour.

2. Is Merkel’s cancer terminal?

MCC, or Merkel cell carcinoma, is a rare skin cancer that may be lethal, killing around 700 individuals each year. It is more likely in those who are often exposed to UV rays. The majority of MCC cases begin with a tiny red or purple bump on the skin.

3. What do large moles imply?

Even a huge mole gets malignant very seldom, and nearly never before the kid enters puberty. Possessing strange moles. Atypical (dysplastic) nevi are moles that are larger than a typical mole and have an irregular form. They are usually inherited.

4. Where can you find Merkel cells?

A kind of cell located just under the epidermis (top layer of skin). These cells are located relatively near to the nerve terminals that receive touch sensations and may be involved in touch.

5. Is the dermis made up of Merkel cells?

The dermis is located underneath the epidermis. Normally, Merkel cells are found in the epidermis. They develop and penetrate the dermis as well as deeper tissues and veins in MCC. (middle), and deeper adipose (fatty) layer.

6. Do Merkel cells have the ability to recognise pain?

Pain, temperature, and touch are examples of somatosensory inputs detected by the peripheral nervous system. Touch receptors consisting of sensory afferents and Merkel cells are known as Merkel receptors.

For more than a century, scientists have debated the significance of Merkel cells in light touch reactions.

7. What exactly are tactile cells?

One of the oval nucleated cells (similar to a Meissner’s corpuscle) that come in close contact with the enlarged ends of nerve fibres in the deeper layers of the epidermis and dermis of various sections of the body and most likely perform a tactile function.

8. Which of the following statements about Merkel cells is correct?

They serve as light-touch sensors. Which of the following is true of free nerve endings? They are sensitive to pain and temperature.

9. How do melanocytes work?

Melanocytes are neural crest-derived cells. They establish a tight interaction with keratinocytes in the human epidermis through their dendrites.

Melanocytes are widely understood for their involvement in skin pigmentation, and their capacity to manufacture and spread melanin has been thoroughly investigated.

10. What are the roles of Merkel and Langerhans cells?

The melanocyte is important for skin pigmentation and UV radiation protection, and it may possibly play a role in cutaneous inflammation control.

The Langerhans cell contributes to the immune surveillance of the body’s exterior surfaces. The Merkel cell is neuroendocrine in nature.

Conclusion

MCs are highly specialised nonkeratinocytes found in the hairy and glabrous skin’s touch-sensitive zones. It is unclear if the cellular origin comes from epidermal components or NCCs. They are essential in mechanoreceptor, neuroendocrine, and nociceptive responses.

Cells with comparable morphologies are found, but their precise roles are unknown. Cell proliferation has been widely reported in brain and keratinocyte hyperplasia disorders. Knowledge of the processes underpinning MC specification will be useful for gaining a better understanding of the disease pathways in which the cells are involved.

It is critical that MCs be studied in detail, both functionally and phenotypically, in this period of increased MC cancer incidence. Years of challenging and fascinating study await the MC research community in order to uncover the intricate molecular pathways underlying human MC biology.

Related Articles