Merkel Cells Are Multimodal Sensory Cells: A Review of Study Methods

Abstract

Merkel cells (MCs) are rare multimodal epidermal sensory cells. Due to their interactions with slowly adapting type 1 (SA1) Aβ low-threshold mechanoreceptor (Aβ-LTMRs) afferents neurons to form Merkel complexes, they are considered to be part of the main tactile terminal organ involved in the light touch sensation. This function has been explored over time by ex vivo, in vivo, in vitro, and in silico approaches. Ex vivo studies have made it possible to characterize the topography, morphology, and cellular environment of these cells. The interactions of MCs with surrounding cells continue to be studied by ex vivo but also in vitro approaches. Indeed, in vitro models have improved the understanding of communication of MCs with other cells present in the skin at the cellular and molecular levels. As for in vivo methods, the sensory role of MC complexes can be demonstrated by observing physiological or pathological behavior after genetic modification in mouse models. In silico models are emerging and aim to elucidate the sensory coding mechanisms of these complexes. The different methods to study MC complexes presented in this review may allow the investigation of their involvement in other physiological and pathophysiological mechanisms, despite the difficulties in exploring these cells, in particular due to their rarity.

Preliminary evidence that Merkel cells exert chemosensory functions in human epidermis

“…Epidermal K8‐, K18‐ or K20‐expressing cells were readily detectable (Figure 1A), albeit not in every section and with high inter‐section and inter‐donor variability. This is in line with the fact that MCs tend to be found in clusters (tactile discs, "Pinkus' Haarscheiben"), rather than being homogeneously distributed 14,15,34 . For subsequent analyses, we focused on those donors in whom at least three MCs across all non‐consecutive sections were detected ( n = 5–6 donors).…”

“…This is in line with the fact that MCs tend to be found in clusters (tactile discs, "Pinkus' Haarscheiben"), rather than being homogeneously distributed. 14,15,34 For subsequent analyses, we focused on those donors in whom at least three MCs across all non-consecutive sections were detected (n = 5-6 donors).…”

“…Although our data strongly point towards a direct effect of Sandalore® on MC activation, we cannot exclude an additive indirect effect induced by mediators released by the neighbouring keratinocytes 51 (Appendix S1). However, while communication between nerve fibres and MCs is well known, 34 direct activation of MCs by keratinocytes in human skin has not yet been proven. In addition, while it has been shown that the effect of Sandalore® on human epidermal and hair follicle keratinocytes are stricktly OR2AT4-mediated, 16,17 this remains to be formally documented for MCs.…”

Cutaneous‐immuno‐neuro‐endocrine (CINE) system: A complex enterprise transforming skin into a super organ

“…By reacting with histamine or activating TRPV4 channels (via VIP) situated on CSANs (Figure 1, Inset), these cells can further suppress the release of other proinflammatory cytokines. 84 In addition, SP released from Merkel cells affects dermal fibroblast proliferation. Thus, Merkel cells influence the local cellular neighbourhood of KCs, CICs, fibroblasts and also share a close partnership with CSANs.…”

“…Thus, Merkel cells influence the local cellular neighbourhood of KCs, CICs, fibroblasts and also share a close partnership with CSANs. 83,84 To add, significant Merkel cell hyperplasia is noted in many skin disorders pointing to their putative role in pathophysiology of those disorders. 84 It is intriguing to observe that despite differences between structure and basic functioning of CSANs and CICs, there is a possible bidirectional communication between them.…”