Merkel Cells

Cells behind a gentle caress

Credit: Art by Nelli Aghekyan. Set in motion by Dr. Emanuele Petretto. Words by Dr. Eshita Paul. Project Coordinator: Dr. Masia Maksymowicz. Series Director: Dr. Radhika Patnala

Sci-Illustrate, Endosymbiont

#Extraordinarycelltypes #sciart #lifescience

Merkel cells: encoding the miracles of touch

’Cause every time we touch, I get this feeling… ♫’ — many of us vibed to this song but did you pause and wonder how does our body help us make sense of touch and interact with the world around us? From a cellular perspective, touch is still the least understood of Aristotle’s five primordial senses, and the fundamental understanding of the machinery behind touch reception is just starting to unfold.

In most vertebrates, Merkel cells (MCs) are one of those extraordinary epithelial cell types that mediate the touch response and tactile acuity (1). Concentrated in touch sensitive areas of the skin and mucosal tissues (such as palms, fingertips, lips, soles), mature MCs are morphologically and functionally distinct from keratinocytes, and account for less than 5% of the total cell population of epidermis (2). Unlike other skin cells, they form physical contact with the low-threshold sensory neurons innervating the epidermis. Together with these Aβ sensory afferents, MCs serve as the mechanosensitive touch transducers of skin, producing tactile discernment (3). Friedrich Sigmund Merkel, a German anatomist and histopathologist, was the first one to discover these epidermal “Tastzellen”, or touch cells, which were later named after him as Merkel cells by Robert Bonnet, a colleague of Dr. Merkel (4).

Origin and Functions of Merkel cells: a nervous affair

Since their discovery, the function of MCs has been debated, and whether they are sensory cells has remained unresolved for more than 130 years. Transcriptome analysis showed that MCs express an array of neuroendocrine and epithelial markers suggesting their participation in both endocrine and nervous actions (5).

Neural function

In mammals, MCs are found in the innermost layer of the epidermis of hairy and glabrous skin. Often they are clustered in various touch sensitive zones called ‘haarscheiben’ or touch domes (also called Iggo-Pinkus domes). Each touch dome has about 10–100 merkel cells which are adjacent to the repeatedly branching slowly adapting type I (SAI) nerve terminals that enter the epidermis (6). MCs together with these nerve endings form the mechanoreceptors that play a role in shaping the light touch response (7). These MC-neurite complexes are also referred to as Merkel’s corpuscle/Merkel endings and they are anatomically similar to neural synapses (8,9).

Endocrine function

Striking similarities to the core granules of the amine precursor uptake and decarboxylation (APUD) system impart endocrine attributes to MCs (1). They secrete a plethora of substances including neuropeptides, neurotransmitters, growth factors, and neuronal cell fate determinants. Interestingly, Merkel cells also express specific epithelial markers such as Krt8, Krt18, and Krt20, as well as enolase which is neuron-specific (3). Immunohistochemical markers for these cells include protein gene product 9.5, synaptophysin, and chromogranin A (10).

Origin

The origin of MCs has also remained ambiguous. While some researchers believe they originate from neural crest cells, others support the theory of their epidermal origin (11, 12). The current consensus is that MCs migrate from both places of origin and become differentiated only once they arrive at the epidermis, with the governance of Atoh1 transcription factor (13). Morphologically, MCs are oval. On one end they connect with the sensory neuritis and on the opposite end, they extend cytoplasmic protrusions to connect with the adjacent keratinocytes through adherens junctions called desmosomal links (14).

Since 1875 till date: Merkel CELLebrations

Over the past decades there has been a phenomenal acceleration in our understanding of touch detection with newer techniques highlighting different skin receptors and their roles in sensing different qualities of touch. Merkel cells are indeed vital for fine motor skills and their age-related degeneration explains the decreasing sensitivity to touch. Any mutation causing their malfunctioning may lead to a pain sensation from a gentle touch and give rise to itching (7). Although recent studies have questioned their association with Merkel cell carcinoma (15), it is indeed worth exploring more deeply the process of Merkel cell fate specification and their complex functionality to better comprehend the disease mechanisms.

Special mention to the Nghiem Lab for arranging the Merkel CELLebration & Dinner each year and sharing with the community the most recent developments in the field of Merkel cell carcinoma (MCC) (Link to 2023 Merkel CELLebration).

Recognizing and appreciating the labs working in this space

1. Laboratory of stem cells and cancer, Université Libre de Bruxelles (ULB), Belgium. https://blanpainlab.ulb.ac.be/
2. SENse Lab, University of California, Berkeley, USA. https://bautistalab.weebly.com/ Twitter: @EllenLumpkin
3. Paul Nghiem Laboratory, University of Washington, USA. https://pnlab.org/ Twitter: @PaulNghiem
4. Galloway Lab, Fred Hutchinson Cancer Research Center, USA. https://research.fredhutch.org/galloway/en/research.html
5. Tissue Biology Research Unit, University Children’s Hospital, Zurich, Switzerland. https://skinterm.eu/key-persons/thomas-biedermann/ Twitter: @SkinTERM_EU
6. Cutaneous Development and Carcinogenesis Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), USA. https://www.niams.nih.gov/labs/brownell-lab
7. Newell Lab, Fred Hutchinson Cancer Research Center, Washington, USA. https://research.fredhutch.org/newell/en.html Twitter: @EvNewell1
8. The Patapoutian Lab, Department of Neuroscience, Howard Hughes Medical Institute, USA. https://patapoutianlab.org/ Twitter: @ardemp
9. Klaus I. Bauman, Department of Functional Anatomy, University of Hamburg, Hamburg, Germany. https://klaus-baumann.de/
10. Masashi Nakatani, Keio University Shonan Fujisawa Campus (SFC) , Kanagawa, Japan. https://www.merkel.jp/ Twitter: Jesse Dery

References

1. Abraham, Jacob, and Sherin Mathew. “Merkel Cells: A Collective Review of Current Concepts.” International Journal of Applied and Basic Medical Research, vol. 9, no. 1, 2019, pp. 9–13. PubMed Central, https://doi.org/10.4103/ijabmr.IJABMR_34_18.
2. Clary, Rachel C., et al. “Spatiotemporal Dynamics of Sensory Neuron and Merkel-Cell Remodeling Are Decoupled during Epidermal Homeostasis.” eLife, vol. 12, May 2023. elifesciences.org, https://doi.org/10.7554/eLife.87368.1.
3. Halata, Zdenek, et al. “Friedrich Sigmund Merkel and His ‘Merkel Cell’, Morphology, Development, and Physiology: Review and New Results.” The Anatomical Record. Part A, Discoveries in Molecular, Cellular, and Evolutionary Biology, vol. 271, no. 1, Mar. 2003, pp. 225–39. PubMed, https://doi.org/10.1002/ar.a.10029.
4. Hartschuh, W., and E. Weihe. “Fine Structural Analysis of the Synaptic Junction of Merkel Cell-Axon-Complexes.” The Journal of Investigative Dermatology, vol. 75, no. 2, Aug. 1980, pp. 159–65. PubMed, https://doi.org/10.1111/1523-1747.ep12522555.
5. Xiao, Ying, et al. “Merkel Cells and Touch Domes: More than Mechanosensory Functions?” Experimental Dermatology, vol. 23, no. 10, 2014, pp. 692–95. Wiley Online Library, https://doi.org/10.1111/exd.12456.
6. Kashgari, Ghaidaa, et al. “Embryonic Development of the Epidermis.” Reference Module in Biomedical Sciences, Elsevier, 2018. ScienceDirect, https://doi.org/10.1016/B978-0-12-801238-3.65811-7.
7. Lumpkin, Ellen A., et al. “The Cell Biology of Touch.” The Journal of Cell Biology, vol. 191, no. 2, Oct. 2010, pp. 237–48. PubMed Central, https://doi.org/10.1083/jcb.201006074.
8. Woo, Seung-Hyun, et al. “Merkel Cells and Neurons Keep in Touch.” Trends in Cell Biology, vol. 25, no. 2, Feb. 2015, pp. 74–81. PubMed Central, https://doi.org/10.1016/j.tcb.2014.10.003.
9. Kabata, Yudai, et al. “The Morphology, Size and Density of the Touch Dome in Human Hairy Skin by Scanning Electron Microscopy.” Microscopy (Oxford, England), vol. 68, no. 3, June 2019, pp. 207–15. PubMed, https://doi.org/10.1093/jmicro/dfz001.
10. Zaccone, G. “Neuron-Specific Enolase and Serotonin in the Merkel Cells of Conger-Eel (Conger Conger) Epidermis. An Immunohistochemical Study.” Histochemistry, vol. 85, no. 1, 1986, pp. 29–34. PubMed, https://doi.org/10.1007/BF00508650.
11. Moll, I., et al. “Intraepidermal Formation of Merkel Cells in Xenografts of Human Fetal Skin.” The Journal of Investigative Dermatology, vol. 94, no. 3, Mar. 1990, pp. 359–64. PubMed, https://doi.org/10.1111/1523-1747.ep12874488.
12. Halata, Z., et al. “Origin of Spinal Cord Meninges, Sheaths of Peripheral Nerves, and Cutaneous Receptors Including Merkel Cells. An Experimental and Ultrastructural Study with Avian Chimeras.” Anatomy and Embryology, vol. 182, no. 6, 1990, pp. 529–37. PubMed, https://doi.org/10.1007/BF00186459.
13. Maricich, Stephen M., et al. “Merkel Cells Are Essential for Light Touch Responses.” Science (New York, N.Y.), vol. 324, no. 5934, June 2009, pp. 1580–82. PubMed Central, https://doi.org/10.1126/science.1172890.
14. Rickelt, Steffen, et al. “Intercellular Adhering Junctions with an Asymmetric Molecular Composition: Desmosomes Connecting Merkel Cells and Keratinocytes.” Cell and Tissue Research, vol. 346, no. 1, Oct. 2011, pp. 65–78. go.gale.com, https://doi.org/10.1007/s00441-011-1260-0
15. DeCaprio, James A. “Molecular Pathogenesis of Merkel Cell Carcinoma.” Annual Review of Pathology: Mechanisms of Disease, vol. 16, no. 1, 2021, pp. 69–91. Annual Reviews, https://doi.org/10.1146/annurev-pathmechdis-012419-032817.

About the author:

DR. ESHITA PAUL

Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories

Dr. Paul did her Ph.D. in Biochemical Engineering (Constructor University, Germany) studying the outer membrane channels and efflux pumps of Gram-negative bacteria in the context of antibiotic resistance. Currently, she is working on pediatric rare genetic disorders at the Centre for DNA Fingerprinting and Diagnostics, India. Dr. Paul is passionate about scientific storytelling and an ardent admirer of scientific illustrations. She enjoys listening to podcasts and decorating the home in her free time.

About the artist:

NELLY AGHEKYAN

Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories

Nelli Aghekyan, did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.

About the animator:

DR. EMANUELE PETRETTO

Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories

Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.

Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.

https://linktr.ee/p3.illustration

About the series:

The League of Extraordinary Cell types

The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.

Sci-Illustrate, Endosymbiont