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Journal of Clinical Medicine

Review The Human Cutaneous Sensory Corpuscles: An Update

Ramón Cobo 1, Jorge García-Piqueras 1,2, Juan Cobo 3,4 and José A. Vega 1,5,*

1 Departamento de Morfología y Biología Celular, Grupo SINPOS, Universidad de Oviedo, 33003 Oviedo, Spain; [email protected] (R.C.); [email protected] (J.G.-P.) 2 Departamento de Anatomía e Histología, Universidad de Zaragoza, 50009 Zaragoza, Spain 3 Instituto Asturiano de Odontología, 33006 Oviedo, Spain; [email protected] 4 Departamento de Cirugía y Especialidades Médico-Quirúrgicas, Universidad de Oviedo, 33006 Oviedo, Spain 5 Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Providencia 7500912, Santiago, Chile * Correspondence: [email protected]; Tel.: +34-985-104097

Abstract: Sensory corpuscles of human are terminals of primary mechanoreceptive associated with non-neuronal cells that function as low-threshold . Structurally, they consist of an extreme tip of a mechanosensory and nonmyelinating peripheral glial cells variably arranged according to the morphotype of the sensory corpuscle, all covered for connective cells of endoneurial and/or perineurial origin. Although the pathologies of sensitive corpuscles are scarce and almost never severe, adequate knowledge of the structure and immunohistochemical profile of these formations is essential for dermatologists and pathologists. In fact, since sensory corpuscles and share a basic structure and protein composition, a cutaneous biopsy may be a complementary method for the analysis of involvement in peripheral neuropathies, systemic diseases, and several pathologies of the central . Thus, a biopsy of cutaneous sensory corpuscles can provide information for the diagnosis, evolution, and effectiveness of treatments of some pathologies in which they are involved. Here, we updated and summarized the current knowledge about the immunohistochemistry of human sensory corpuscles with the aim to provide information to dermatologists and skin pathologists.

  Keywords: skin sensory innervation; sensory corpuscles; Meissner corpuscles; Ruffini corpuscles;

Citation: Cobo, R.; García-Piqueras, Pacinian corpuscles; human J.; Cobo, J.; Vega, J.A. The Human Cutaneous Sensory Corpuscles: An Update. J. Clin. Med. 2021, 10, 227. https://doi.org/10.3390/jcm10020227 1. Introduction The body surface of mammals is covered by two structurally different types of skin, Received: 7 December 2020 i.e., nonhairy or glabrous and hairy skin. Glabrous skin contains no , has a thick Accepted: 8 January 2021 epidermal layer, and is restricted to zones characterized by high discriminative touch Published: 10 January 2021 (shape, size, texture) such as the palms of hands or the plantar surfaces of the feet. Hairy skin covers more than 90% of the body surface, has a thin epidermal layer, and is strongly Publisher’s Note: MDPI stays neu- associated with affective touch [1]. Glabrous skin contains three types of sensory corpuscles, tral with regard to jurisdictional clai- which have more or less specific tactile tuning properties: Meissner corpuscles, Ruffini ms in published maps and institutio- corpuscles, and Pacinian corpuscles. Furthermore, it contains sensory –neurite nal affiliations. complexes related to touch detection, but they are not sensory corpuscles sensu stricto (Figures1 and2 )[1–4]. These sensory structures work as low-threshold mechanoreceptors (LTMRs) in connection with a subpopulation of primary mechanosensory neurons whose Copyright: © 2021 by the authors. Li- bodies are localized in the dorsal root ganglia and the sensory ganglia of the cranial censee MDPI, Basel, Switzerland. nerves [1,5]. LTMR nerve fibers are classified as Aβ,Aδ, or C based on their axon diameter, This article is an open access article degree of myelination, and conduction velocities [3,5]. Functionally, LTMRs distributed under the terms and con- fall into two categories, rapidly adapting (RA) and slowly adapting (SA) mechanoreceptors, ditions of the Creative Commons At- which each have two variants: type I and type II [6,7]. Morphologically, they correspond tribution (CC BY) license (https:// with Meissner and Pacinian corpuscles (RAI and RAII, respectively), Merkel cell–neurite creativecommons.org/licenses/by/ complexes (SAI), and dermal Ruffini corpuscles (SAII) [1]. 4.0/).

J. Clin. Med. 2021, 10, 227. https://doi.org/10.3390/jcm10020227 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 13

J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 13

J. Clin. Med. 2021, 10, 227 mechanoreceptors, which each have two variants: type I and type II [6,7]. Morphologi-2 of 12 cally, they correspond with Meissner and Pacinian corpuscles (RAI and RAII, respec- tively), Merkelmechanoreceptors, cell–neurite complexes which each (SAI) have, and two d ermalvariants Ruffini: type corpuscles I and type (SAII)II [6,7]. [1]. Morphologi- cally, they correspond with Meissner and Pacinian corpuscles (RAI and RAII, respec- tively), Merkel cell–neurite complexes (SAI), and dermal Ruffini corpuscles (SAII) [1].

FigureFigure 1. 1. ((AA)) Schematic representation representation showing showing the the structure structure of the of theskin skin and andthe different the different morphotypes morphotypes of sensory of sensory cor- corpuscles.puscles. 1: 1:Meissner MeissnerFigure 1.corpuscles; corpuscles;(A) Schematic 2: 2:Ruffini Ruffinirepresentation corpuscles; corpuscles; showing 3: 3:Pacini Pacini the corpuscles structure corpuscles; of; ( Bthe ()B l )owskin low magnification and magnification the different of ofa morphotypeshistological a histological section of section sensory cor- of human digital skin. The lines indicate the approximate limits of the three skin layers (epidermis, dermis—papillary and of human digitalpuscles. skin. 1: The Meissner lines indicatecorpuscles; the 2: approximateRuffini corpuscles; limits 3: of Pacini the threecorpuscles skin; layers (B) low (epidermis, magnification dermis—papillary of a histological section reticular—andof hypodermis). human digital Bothskin. theThe dermislines indicate and hypodermis the approximate contain limits abundant of the three sensory skin layerscorpuscles. (epidermis, * denote dermiss Pacinian—papillary and and reticular—and hypodermis). Both the dermis and hypodermis contain abundant sensory corpuscles. * denotes corpuscles. reticular—and hypodermis). Both the dermis and hypodermis contain abundant sensory corpuscles. * denotes Pacinian Pacinian corpuscles.corpuscles.

Figure 2. Section of human digital skin immunostained for the demonstration of -specific enolase that labels Figure 2. SectionFigure of human 2. Section digital of skin human immunostained digital skin for immunostained the demonstration for of the neuron demonstration-specific enolase of neuron-specific that labels axons in nerve fibersin and nerve sensory fibers corpusclesand sensory as corpuscles well as Merkel as well cells. as Merkel FNE: cells.free nerve FNE: freeending nerve (wh endingite arrows); (white MC: arrows); Meissner MC: Meissner cor- cor- enolase that labels axons in nerve fibers and sensory corpuscles as well as Merkel cells. FNE: free puscles (blackpuscles arrows); (black Mc- NC:arrows); Merkel Mc- NC:cell– Merkelneurite cellcomplex–neurite (red complex arrows). (red bv: arrows). blood vessels;bv: blood e: vessels;epidermis. e: epidermis. nerve ending (white arrows); MC: Meissner corpuscles (black arrows); Mc-NC: Merkel cell–neurite complexThe (red peripheral arrows).The peripheralprocesses bv: blood vessels;ofprocesses Aβ LTMRs e: epidermis.of Aβ contact LTMRs in contact the skin in withthe skin specialized with specialized epithelial epithelial cells, i.e., Merkelcells, i.e. cells, Merkel, to form cells M, toerkel form cell M–erkelneurite cell complexes–neurite complexes (which are (which not includedare not included in in β this review)The peripheralthis or review)with processesglial or Schwannwith ofglial A- likeSchwannLTMRs cells - contacttolike form cells inpart to the form of skin the part withsensory of the specialized corpusclessensory corpuscles epithelial [2,8]. [2,8]. cells,Structurally, i.e., MerkelStructurally, all cutaneous cells, toall form cutaneoussensory Merkel corpuscles sensory cell–neurite corpuscles consist complexes of consist a dendritic of (which a dendritic zone are corresponding not zone included corresponding in thisto the review) extremeto or the tip with extreme of glialthe peripheral tip Schwann-like of the peripheral process cells of process toan formAβ- ofLTMR part an Aβ ofsurrounded-LTMR the sensory surrounded by corpuscles nonmyelinat- by nonmyelinat- [2,8]. Structurally,ing glial cellsing all variably glial cutaneous cells arranged variably sensory, arrangedboth corpuscles contained, both consist contained in a more of a dendriticin or a lessmore developed zoneor less corresponding developed capsule capsulere- to re- thelated extreme to endoneurial/perineuriallated tip of to the endoneurial/perineurial peripheral cells process [9–12 of cells]. an Thus, A[9β–12-LTMR periaxonal]. Thus, surrounded periaxonal cells are by cellscontinuous nonmyelinating are continuous with with glialthe cells cells of variably thenerve cells trunks, arranged,of nerve demonstrating trunks, both contained demonstrating a relationship in a morea relationship between or less developed betweennerves and nerves capsule the andcompo- related the compo- tonents endoneurial/perineurial that formnents sensory that form corpuscles sensory cells [corpuscles 9[9,10].–12]. Considering Thus, [9,10]. periaxonal Considering Pacinian cells Paciniancorpuscles are continuous corpuscles as a paradigm withas a paradigm the cellsof the of continuity nerveof the trunks, continuitybetween demonstrating nerves between and nerves acorpuscular relationship and corpuscular components, between components, nerves the capsule and the the andcapsule components the andouter the outer that form sensory corpuscles [9,10]. Considering Pacinian corpuscles as a paradigm of the continuity between nerves and corpuscular components, the capsule and the outer core are continuous with the , the intermediate layer is related to the , and the inner core corresponds to the Schwann cells [11,13]. Filling the spaces among J. Clin. Med. 2021, 10, 227 3 of 12

cell layers is a chemically complex extracellular matrix, sometimes organized as a basal lamina [14–18]. In this review, we updated and summarized the current knowledge about the im- munohistochemistry of human cutaneous sensory corpuscles with the aim to provide complete information to dermatologists and skin pathologists. The pathologies of cuta- neous sensory corpuscles are rarely severe. However, detailed knowledge of their structure and immunohistochemical profile may be of interest because they can be quantitatively and/or qualitatively altered in some local pathologies (such as Dupuytren’s syndrome or neurofibromes) and systemic pathologies (diabetic neuropathy, human immunodeficiency virus neuropathy), and diseases (among them, Parkinson’s disease, amyotrophic lateral sclerosis, and Guillain-Barré syndrome, as well as some psychiatric disorders and mental deficiencies) (for a review, see [19,20]). Consistently, cutaneous sen- sory corpuscles have gained interest since their biopsy can provide information on the diagnosis, evolution, and effectiveness of treatments of some of the pathologies in which they are involved [20–23]. Furthermore, because sensory corpuscles and nerves share a basic structure and protein composition, a cutaneous biopsy may be a complementary method for the analysis of nerve involvement in peripheral neuropathies, systemic diseases, and several pathologies of the central nervous system. Although there are recent reviews on sensory corpuscles [1,10], none incorporate the new data related to their protein composition that occurred in the last 10 years, especially in humans. For this reason, we considered that it may be relevant to carry out an up-to- date review of the subject. In addition, this review is included in the Special Issue of the Journal of Clinical Medicine devoted to the “Structure and Function of Human Cutaneous Sensory Corpuscles” and is intended to be the starting point for a better understanding of other contributions. The following sections detail the structure and protein composition of Meissner, Pacinian, and Ruffini corpuscles, as well as other less frequent morphotypes, of the human glabrous skin.

2. Meissner Corpuscles Meissner corpuscles exist only in humans and primates, although Meissner-like cor- puscles have been described in several mammal species [8]. They are typical of glabrous skin and are concentrated in skin areas especially sensitive to discriminative fine touch (fingertips, palm, soles of the feet, lips, and male and female genital skin) and occasionally on the tongue and palate [8]. They are located just below the epidermis, in the dermal papillae of the papillary dermis. Although their morphology and size are largely variable, they frequently have an oval shape with a larger axis perpendicular to the surface of the skin. Meissner corpuscles commence differentiation at around 20 weeks of estimated gestational age (wega), show basic morphology by 36 wega, and acquire a definitive aspect and immunohistochemical profile postnatally [24]. However, the density of Meissner corpuscles is not stable throughout their life, and their number and size are reduced with age [25]. Meissner corpuscles consist of an axon, nonmyelinating glial cells (denominated laminar cells regarded as modified and specialized Schwann cells), and a capsule of fibroblasts of endoneurial origin (Figures3 and4)[ 10,12]. The axon is usually unique, although, occasionally, one or two accessory axons can be found. In Macaca fascicularis and Macaca mulata, the main axon is an Aβ fiber, and the accessories are C or Aδ fibers [26]. Very recently, in mice, Neubarth and coworkers [27] observed that murine Meissner-like corpuscles are innervated by two subtypes that exhibit distinct responses to tactile stimuli. Whether or not this also occurs in humans remains to be demonstrated. The sheath that envelops the axon is lost upon entering the corpuscle [28], but the axon is always in relation to the laminar cells arranged as stacks of flattened sheets (classically described as a “coin stack”) usually arranged parallel to the skin surface. Between the laminar cells and the axon, there is an extracellular matrix of a very complex J. Clin. Med. 2021, 10, 227 4 of 12

J. Clin. Med. 2021, 10, x FOR PEER REVIEW 4 of 13 chemical composition [16,18]; isolating the corpuscle, there is a capsule of endoneurial J. Clin. Med. 2021, 10, x FOR PEER REVIEW 4 of 13 nature [12].

Figure 3.3. Immunohistochemical profile profile of humanhuman cutaneouscutaneous MeissnerMeissner corpuscles.corpuscles. ImmunohistochemicalImmunohistochemical localization of Figure 3. Immunohistochemical profile of human cutaneous Meissner corpuscles. Immunohistochemical localization of S100 protein ( (S100),S100), neuron neuron-specific-specific enolase ( (NSE),NSE), CD34 CD34,, Glut Glut-1,-1, vimentin ( (VIM),VIM), neurofilament protein (NFP), lumican (LUM)S100 protein and PIEZO2 (S100), inneuron human-specific digital enolase Meissner (NSE corpuscles), CD34,. (Gluta,b)- S1,erial vimentin sections (VIM of the), neurofilament same corpuscle protein showing (NFP), the lamellarlumican (LUM) and PIEZO2 in human digital Meissner corpuscles. (a,b) Serial sections of the same corpuscle showing the cells(LUM) (S100 and-protein PIEZO2-positive) in human and digital the axon Meissner (NSE corpuscles-positive); .( c(a) ,immunolabelingb) Serial sections ofof thethe endoneurialsame corpuscle capsule showing (CD34 the-positive); lamellar lamellar cells (S100-protein-positive) and the axon (NSE-positive); (c) immunolabeling of the endoneurial capsule (CD34- (cellsd–f) (S100 images-protein of double-positive) immunofluorescence and the axon (NSE demonstrating-positive); (c) thatimmunolabeling S100P and VIM of thecolocalize endoneurial in lamellar capsule cells. (CD34 (g,h-)positive); variable relationships(positive);d–f) images (d– fofof) imagesdouble the axon ofimmunofluorescence double(NFP-positive) immunofluorescence with demonstrating the lamellar demonstrating cells that (S100PS100P that -and or S100P VIM- andcolocalizepositive); VIM colocalize (ini,j )lamellar endoneurial, in cells. lamellar (butg,h cells. )no variablet peri- (g,h) neurial,relationshipsvariable nature relationships of of the the axon capsule of the (NFP axon in-positive) Meissner (NFP-positive) with corpuscle the with lamellars (CD34 the lamellar cells-positive; (S100P cells arrows);- (S100P- or VIM ( ork-positive);) VIM-positive);expression (i,j )of endoneurial, lumican, (i,j) endoneurial, a component but no butt peri- not of theneurial,perineurial, extracellular nature nature of matrix, the of thecapsule in capsule association in Meissner in Meissner with corpuscle the corpuscles lamellars (CD34 (CD34-positive; cells;-positive; (l) expression arrows); arrows); of(k )PIEZO2 (expressionk) expression, a mechanoprotein of lumican, of lumican, a component a involved component ofin mechanotransductiontheof the extracellular extracellular matrix, matrix, in inthe inassociation axon association of Meissner with with the thecorpuscles. lamellar lamellar cells; ed: cells; epidermis; (l ()l )expression expression MC: ofMeissner of PIEZO2 PIEZO2, corpuscles, a a mechanoprotein mechanoprotein. bv: blood involved vessels (inin c)mechanotransduction. inin thethe axon axon of of Meissner Meissner corpuscles. corpuscles. ed: ed: epidermis; epidermis; MC: MC: Meissner Meissner corpuscles. corpuscles bv:. b bloodv: blood vessels vessels (in ( c(in)). c).

Figure 4. Schematic representation of Meissner corpuscles showing the proteins detected in the different corpuscular com- ponentsFigure 4. 4. using SchematicSchematic immunohistochemistry. representation representation of ofMeissner Axon Meissner: yellow corpuscles corpuscles box, showinglamellar showing thecells theproteins: purple proteins detected box, detected capsule in the: in pinkdiffere the box differentnt. corpuscular corpuscular com- ponentscomponents using using immunohistochemistry. immunohistochemistry. Axon Axon:: yellow yellow box,box, lamellar lamellar cells cells:: purple purple box, box, capsule capsule:: pink pink box box.. The myelin sheath that envelops the axon is lost upon entering the corpuscle [28], but the axonTheFunctionally, myelinis always sheath Meissnerin relation that envelops corpuscles to the laminarthe are axon RA cells is I-LTMRs lost arranged upon that entering as detect stacks the fine ofcorpuscle touch.flattened For [28] sheets many, but (classicallythyears,e axon they is described werealways exclusively in asrelation a “coin related to stack the to laminar”) the usually detection cells arranged arranged and discrimination parallel as stacks to the of of skinflattened low-frequency surface. sheets Be- tween(classicallyvibration; the however,laminar described cells they as andaare “coin the also stackaxon responsible”, )there usually is for an arranged theextracellular detection parallel ofmatrix fineto the movementsof skin a very surface. complex on Be- the chemicaltweenskin [29 the]. composition Furthermore,laminar cells [16,18] Meissner and the; isolating axon corpuscles, there the have corpuscleis an been extracellular, proposed there is matrixa to capsule function of aof asv eryendoneurial , complex naturechemical [12]. composition [16,18]; isolating the corpuscle, there is a capsule of endoneurial natureFunctionally [12]. , Meissner corpuscles are RA I-LTMRs that detect fine touch. For many years,Functionally they were exclusively, Meissner corpusclesrelated to the are detection RA I-LTMRs and dithatscrimination detect fine oftouch. low- frequencyFor many years, they were exclusively related to the detection and discrimination of low-frequency

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J. Clin. Med. 2021vibration, 10, 227 ; however, they are also responsible for the detection of fine movements on the 5 of 12 skin [29]. Furthermore, Meissner corpuscles have been proposed to function as nocicep- tors,vibration as accessory; however, axons they express are also neuropeptides responsible for relat the eddetection to nociception of fine movements [26], and on evidence the skin [29]. Furthermore, Meissner corpuscles have been proposed to function as nocicep- is being accumulatedas accessory that not axons only expressaxons but neuropeptides also lamellar related cells to are nociception touch sensors [26], and [30]. evidence is being tors, as accessory axons express neuropeptides related to nociception [26], and evidence accumulated that not only axons but also lamellar cells are touch sensors [30]. is being accumulated that not only axons but also lamellar cells are touch sensors [30]. 3. Ruffini Corpuscles 3. Ruffini Corpuscles 3.Ruffini Ruffini corpuscles Corpuscles (Fig ures 5 and 6) or endings are elongated, spindle-shaped for- Ruffini corpuscles (Figures5 and6) or endings are elongated, spindle-shaped forma- mations, Ruffiniwith a corpuscleslengthtions, of with u(Figp a to lengthures 2 mm 5 ofand and up 6) to a or 2transverse mmendings and aare dimension transverse elongated, dimension of spindle 150 m- in ofshaped 150their m for-central in their central or or equatorialmations, with portion aequatorial length and of 40 portionu pm to at 2 extreme mm and and 40 m lossesa attransverse extreme or poles. lossesdimension They or poles. areof 150 distributed They m in are their distributed incentral the der- in the dermis, mis, orligaments equatorial, and portionligaments, joint and capsules and40 m joint at [1,2]. extreme capsules In human losses [1,2 ].or digital In poles. human skinThey digital, arethey distributed skin, are scarce they arein, withthe scarce, der- a den- with a density sity smallemis, ligamentsr than 0.3,smaller and corpuscles/mm joint than capsules 0.3 corpuscles/mm [1,2].2 [31]. In human2 [ 31digital]. skin, they are scarce, with a den- sity smaller than 0.3 corpuscles/mm2 [31].

Figure 5. Immunohistochemical profile of human cutaneous Ruffini corpuscles. Immunohistochem- FigureFigure 5. Immunohistochemicalical 5. localization Immunohistochemical of S100 profile protein ofprofile ( humana–d) in of dermal cutaneoushuman Ruffini cutaneous Ruffini corpuscles corpuscles. Ruffini show corpuscles. Immunohistochemicals different Immunohistochem- aspects depend- localization of S100 proteinical localizationing (a –ond) the in dermal section of S100 Ruffiniof theprotein corpuscle, corpuscles (a–d )and showsin dermalthe differentthickness Ruffini aspects of thecorpuscles capsule depending is show also on variables the different section. (e) of aspectsSurrounding the corpuscle, depend- and the thicknessing ofonthe the the inner capsule section nucleus is of also the (S100 variable. corpuscle,-positive (e) Surrounding andcells) the of thicknessRuffini the innercorpuscles of nucleus the capsule, there (S100-positive is is a also capsule variable cells) (CD34 of. Ruffini(-epositive)) Surrounding corpuscles, of there is a capsulethe innerendoneurial (CD34-positive) nucleus nature (S100 of; endoneurial c-:positive capsule; incells) nature;: inner of c: nucleus.Ruffini capsule; corpuscles in: inner nucleus., there is a capsule (CD34-positive) of endoneurial nature; c: capsule; in: inner nucleus.

Figure 6. SchematicFigure 6. Schematic representation representation of Ruffini of corpusclesRuffini corpuscles showing showing the proteins the proteins detected detected in the in different the dif- corpuscular ferent corpuscular components using immunohistochemistry. Axon: yellow box; lamellar cells: components using immunohistochemistry. Axon: yellow box; lamellar cells: purple box; capsule: pink box. purple box; capsule: pink box. Figure 6. Schematic representationStructurally, of they Ruffini consist corpuscles of tree branchesshowing ofthe a singleproteins axon detected embedded in the in dif- peripheral glial ferent corpuscularStructurally, componentscells they without consist using any of organization immunohistochemistry.tree branches and ofcollagen a single Axon: fibersaxon yellow thatembedded have box continuity; lamellarin peripheral cells: in both poles of the purpleglial box cells; capsule: withoutextracorpuscular pink any box. organization dermis. and collagen Surrounding fibers and that isolating have continuity the corpuscle in both is apoles capsule consisting of the extracorpuscularof four or dermis. five layers Surrounding of endoneurial and isolating cells [31 ,the32]. corpuscle is a capsule con- sistingStructurally, of four orthey fivePreviously, consist layers of of endoneurialRuffini tree branches corpuscles cells of [31,32]. were a single considered axon embedded , in peripheral but recent evidence glial cells withoutsuggests any organization that they could and alsocollagen play afibers role in that detecting have continuity tactile stimuli in (stretching,both poles roughness) of the extracorpuscular dermis. Surrounding and isolating the corpuscle is a capsule con- sisting of four or five layers of endoneurial cells [31,32].

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Previously, Ruffini corpuscles were considered thermoreceptors, but recent evidence andsuggests represent that II-LTMRsthey could also [1]. play However, a role in at detecting least in tactile humans, stimuli there (stretching, is a mismatch roughness) between physiologicaland represent and II- histologicalLTMRs [1]. However, studiessince, at least although in humans, electrophysiological there is a mismatch studies between demon- stratephysiological that glabrous and histological skin shows studies abundant since, SAalthough type II-LTMRs,electrophysiological histologically, studies theydemon- are very scarce.strate For that example, glabrous inskin humans, shows abundant a single Ruffini-likeSA type II-LTMRs corpuscle, histologically was reported, they are in thevery skin of thescarce. index For finger, example which, in ishumans much, lessa single than Ruffini what-like would corpuscle be expected was reported based in on the physiological skin of recordingsthe index [finger7,33]., which For this is much reason, less the than correlation what would between be expected Ruffini based corpuscles on physiological and slowly adaptedrecordings mechanoreception [7,33]. For this reason, has been the correlation questioned, between and thereRuffini are corpuscles likely to and be slowly other nerve formationsadapted mechanoreception responsible or coresponsible has been questioned for it [34, and]. there are likely to be other nerve formations responsible or coresponsible for it [34]. 4. Pacini (Pacinian) Corpuscles 4. Pacini (Pacinian) Corpuscles Pacini corpuscles are large, ovoid formations (up to 5 × 3 mm) largely distributed in most organsPacini and tissues, corpuscles including are large the, ovoid deep formations dermis and (up hypodermis to 5 × 3 mm) ( Figureslargely distributed1B,7 and8 in) [8,35]. most organs and tissues, including the deep dermis and hypodermis (Figures 1B, 7, and In human digital skin, the development of Pacinian corpuscles begins at 13 wega and is 8) [8,35]. In human digital skin, the development of Pacinian corpuscles begins at 13 wega completedand is completed at four monthsat four months of life, of although life, although their basictheir basic structure structure and and immunohistochemical immunohisto- characteristicschemical characteristics are reached are at reached 36 wega. at 36 During wega. During development, development, around around the axon,the axon, a complex a networkcomplex of network S100-positive of S100- Schwann-cell-relatedpositive Schwann-cell-related processes processes is progressively is progressively compacted com- to formpacted the innerto form core, the in andner thecore, surrounding and the surrounding mesenchyme mesenchyme organizes organize to forms to theform outer the core andouter the core capsule and the [24 ].capsule On the [24]. other On the hand, other Pacinian hand, Pacinian corpuscles corpuscles generally generally show show no relevantno age-relatedrelevant age alterations-related alterations [25]. [25].

FigureFigure 7. Immunohistochemical 7. Immunohistochemical profile profile of of human human cutaneous cutaneous PacinianPacinian corpuscles. corpuscles. Immunohistochemical Immunohistochemical localization localization of of neurofilamentneurofilament proteins proteins (NFP), (NFP) S100, S100 protein protein (S100P), (S100P), acid-sensing acid-sensing ion ion channel channel 2 (ASIC2), 2 (ASIC2), PIEZO2, PIEZO2, CD34 CD34 and vimentin and vimentin in in human digital Pacinian corpuscles. Pacinian corpuscles are divided into two main compartments: the neural compartment human(N digitalC), which Pacinian comprises corpuscles. the axonPacinian and the glial corpuscles cells, and are the divided non-neural into compartment two main compartments: (n-NC), which thecomprises neural both compartment the (NC),outer which core comprises and the capsule the axon of perineurial and the glial origin. cells, Both and compartments the non-neural are separated compartment by an intermediate (n-NC), which layer comprisesof endoneurial both the outer coreorigin. and All the the capsulePacinian ofcorpuscle perineurial constituent origin.s ca Bothn be compartments selectively immunolabeled. are separated (a) byThe an axon intermediate displaying i layermmunoreactiv- of endoneurial origin.ity All for the NFP; Pacinian (b) the corpuscle inner core constituents lamellae are canS100 beP immunoreactive; selectively immunolabeled. (c,d) occurrence (a) of The the axon mechanoproteins displaying immunoreactivity ASIC2 and for NFP; (b) the inner core lamellae are S100P immunoreactive; (c,d) occurrence of the mechanoproteins ASIC2 and PIEZO2, respectively, in the axon; a faint immunoreactivity for ASIC2 is also present in the inner core; (e–g) double immunofluorescence, demonstrating that lamellar cells forming the inner core display the S100P and are covered by a layer of endoneurial-related cells (CD34-positive), the so-called intermediate layer; (h–j) double immunofluorescence, demonstrating that the lamellar system of Pacinian corpuscles (inner core, intermediate later, outer core, capsule) display vimentin and the division of Pacinian corpuscles into NC (within the CD34+ intermediate layer) and n-NC. Ax: axon; c: capsule; ic: inner core; il: intermediate layer; oc: outer core. J. Clin. Med. 2021, 10, x FOR PEER REVIEW 7 of 13

PIEZO2, respectively, in the axon; a faint immunoreactivity for ASIC2 is also present in the inner core; (e–g) double im- J. Clin.munofluorescence Med. 2021, 10, 227 , demonstrating that lamellar cells forming the inner core display the S100P and are covered by a layer7 of 12 of endoneurial-related cells (CD34-positive), the so-called intermediate layer; (h–j) double immunofluorescence, demon- strating that the lamellar system of Pacinian corpuscles (inner core, intermediate later, outer core, capsule) display vi- mentin and the division of Pacinian corpuscles into NC (within the CD34+ intermediate layer) and n-NC. Ax: axon; c: capsule; ic: inner core; il: intermediate layer; oc: outer core.

Figure 8. SchematicSchematic representation representation of of Pacinian Pacinian corpuscles corpuscles showing showing the theproteins proteins detected detected in the in different the different corpusc corpuscularular com- componentsponents using using immunohistochemistry. immunohistochemistry. Axon: Axon: yellow yellow box; box;lamellar lamellar cells: cells: purple purple box; box;capsule: capsule: pink pink box; box;extracellular extracellular ma- matrix:trix: white white box. box.

Cells forming PacinianPacinian corpusclescorpuscles areare typically typically arranged arranged around around the the axon, axon showing, showing a atypical typical appearance appearance of of an an “onion “onion bulb” bulb” (Figures (Figures7 7and and8). 8). Within Within the the laminar laminar formations formations can be be distinguished distinguished two two compartments compartments called called the the inner inner core core and and the the outer outer core; core; both both are surroundedare surrounded by a byfibrous a fibrous capsule capsule of varying of varying thickness. thickness. In the central In the part central of the part inner of core the isinner the axon core o isf an the Aβ axon-LTMR of an, which Aβ-LTMR, is directly which surrounded is directly and surrounded attached to andnonmyelinating attached to Schwannnonmyelinating-like cells Schwann-like denominated cells laminar denominated cells (neural laminar compartment) cells (neural compartment)[35]. Among these [35]. Amonglamellae these is a molecularly lamellae is acomplex molecularly extracellular complex matrix extracellular [17,18]. matrix Occasionally, [17,18]. Pacinian Occasionally, cor- pusclesPacinian contain corpuscles additional contain C additional or Aδ fibers C, or which Aδ fibers, are thought which areto be thought sensory to or be postgangli- sensory or postganglioniconic sympathetic sympathetic (see [36]). (see [36]). The non-neuralnon-neural compartment of the corpuscles is divided into an outer core and a capsule. TheThe outerouter core core consists consists of of flattened flattened fibroblast-like fibroblast-like cells, cell whichs, which completely completely surround sur- roundthe inner the core. inner Between core. Between the inner the and inner the and outer the cores, outer there cores is, anthere intermediate is an intermediate cell stratum, cell stratumthe cellular, the elementscellular elements of which of are which modified are modified endoneural endoneural fibroblasts fibroblasts [11]. Finally, [11]. Finally, on the onoutside the outside of the corpuscle, of the corpuscle there is, athere capsule is a of capsule variable of thickness, variable thickness, which, like which the outer, like core, the outercomes core, from comes the perineurium. from the perineurium. Typically, the Typically, capsule contains the capsule capillaries contains and capillaries macrophages. and macrophageFunctionally,s. Pacini corpuscles are representative of RA II-LTMRs and respond to pressureFunctionally, and vibratory Pacini stimuli corpuscle betweens are 20representative and 1500 Hz, of with RA II a- maximumLTMRs and sensitivity respond atto pressure200–400 Hzand [6 vibratory,7,34]. stimuli between 20 and 1500 Hz, with a maximum sensitivity at 200–400 Hz [6,7,34]. 5. Other Morphotypes of Sensory Corpuscles In addition to the above-mentioned main types of cutaneous sensory corpuscles, other morphotypes have been identified in the skin. Corpuscles receptors defined by light microscopy include Krause end-bulbs and Golgi–Mazzoni corpuscles (Figure9).

J. Clin. Med. 2021, 10, x FOR PEER REVIEW 8 of 13

5. Other Morphotypes of Sensory Corpuscles

J. Clin. Med. 2021, 10, 227 In addition to the above-mentioned main types of cutaneous sensory corpuscles,8 of 12 other morphotypes have been identified in the skin. Corpuscles receptors defined by light microscopy include Krause end-bulbs and Golgi–Mazzoni corpuscles (Figure 9).

FigureFigure 9.9. ImmunohistochemicalImmunohistochemical localization of neurons specificspecific enolaseenolase (NSE),(NSE), neurofilamentneurofilament proteinprotein (NFP)(NFP) andand S100S100 proteinprotein (S100P)(S100P) in in possible possible Krause Krause corpuscles corpuscles (a– (da),–d Golgi–Mazzoni), Golgi–Mazzoni corpuscles corpuscles (e,f) ( ande,f) aand cluster a cluster of small of lamellarsmall lamellar corpuscles cor- (pusclesg,h). Axons (g,h) display. Axons strongdisplay immunoreactivity strong immunoreactivity for NSE andfor NSE NFP, and and NFP Schwann-like, and Schwann cells-like are S100P-positive.cells are S100P-positive (b–d) double. (b- immunofluorescenced) double immunofluorescence demonstrating demonstrating NFP- and NFP S100P-immunoreactivity- and S100P-immunoreactivity in axons andin axons glial cells,and glial respectively cells, respectively in possible in possible Krause corpuscles. Krause corpuscles.

Krause corpuscles or bulbs are encapsulated sensorysensory corpusclescorpuscles occurringoccurring inin thethe skinskin and mucous membranes, previously regarded as sensory cold receptors. Structurally Structurally,, theythey present inin glabrous skinskin andand areare mademade upup of axon endings sheathed by Schwann-likeSchwann-like cellscells contained in in a a fine fine fibroblastic fibroblastic capsule. capsule. Occasionally Occasionally,, they they have have additional additional thin thinaxons axons with withdense dense-core-core vesicles. vesicles. Many Many authors authors consider consider Krause Krause end-bu end-bulbslbs as clusters as clusters of free of nerve free nerveendings. endings. The term Golgi–MazzoniGolgi–Mazzoni corpuscles has been used to describe aa similarsimilar structurestructure toto Pacinian corpuscles found only inin thethe fingertips.fingertips. TheyThey consistconsist ofof completelycompletely concentricconcentric lamellae resemblingresembling small small Pacinian Pacinian corpuscles corpuscles and and have have also also been been called called simple simple corpuscles. corpus- Theycles. They have have few lamellae few lamellae in the in outer the core–capsuleouter core–capsule system, system, and the and asymmetrical the asymmetrical position po- of thesition inner of the core inner cells core around cells the around axon tip the is axon a typical tip is characteristic a typical characteristic of this kind of of this mechanore- kind of ceptor.mechanoreceptor. They differ T fromhey Paciniandiffer from corpuscles Pacinian because corpuscles of their because smaller of their dimensions, smaller surfacedimen- positionsions, surface in the position dermis, considerablyin the dermis, thinner considerably capsule, thinner the frequent capsule, presence the frequen of twot presence afferent myelinatedof two afferent nerve myelinated fibers, and nerve the absence fibers, and of capillaries the absence on of the capillaries capsule [1 on–3 ].the capsule [1– 3]. 6. Proteins in Human Sensory Corpuscles 6. ProteinsCutaneous in Human sensory Sensory corpuscles Corpuscles have a very complex and heterogeneous protein con- tent,Cutaneous as demonstrated sensory in corpuscles numerous have studies a very performed complex for and more heterogeneous than 40 years protein based con- on immunohistochemicaltent, as demonstrated in data. numerous In recent studies years, performed the study offor Meissner more than corpuscles 40 years and,based to on a lesserimmunohistochemical extent, other kinds data. of In cutaneous recent years, sensory the corpuscles,study of Mei wasssner added corpuscles to the and study, to of a peripherallesser extent, neuropathies other kinds as of an cutaneous additional sensory method corpuscles, in the substitution was added of to nerve the study biopsy of [ 20pe-]. Therefore,ripheral neuropathies it is important asto an understand additional not method only thein numericalthe substitution or morphological of nerve biopsy variations [20]. but also their protein composition of the sensory corpuscles. All available data on proteins present in sensory corpuscles were obtained using immunohistochemistry techniques, and references for papers reporting each of those proteins are included in the reviews by Vega’s Lab [9,10,19,37,38] and Pawson et al. (Figures4,6 and8)[31]. J. Clin. Med. 2021, 10, 227 9 of 12

The axon supplying sensory corpuscles displays immunoreactivity for neuron or neuroendocrine markers such as the protein gene product 9.5 (PGP 9.5) and neuron-specific enolase (NSE). The axon also contains neurofilament proteins. The glial fibrillary acidic protein (GFAP) could theoretically be considered the interme- diate filament protein filling the cytoplasm of the Schwann-related cells forming sensory corpuscles. However, we observed the absence of GFAP immunoreactivity in human cutaneous sensory corpuscles. By contrast, the lamellar cells of the Meissner corpuscles and the inner core of the Pacinian cones display vimentin immunoreactivity. Vimentin was also detected in the outer core and capsule of the human cutaneous Pacinian corpuscles. Several calcium-binding proteins that participate in mechanoreceptor electrogenesis have been found in human sensory corpuscles. S-100 protein is localized in the lamellar cells of Meissner corpuscles and the inner core lamellae of Pacinian corpuscles. Calbindin D28, calretinin, parvalbumin, and neurocalcin are localized in the central axon and the glial cells of Meissner and Pacinian corpuscles. Growth factors are substances that stimulate cells to divide or increase in size and have effects on cell differentiation as well as on the acquisition and maintenance of the neuronal phenotype. Several growth factors and their cognate receptors have been detected in human cutaneous sensory corpuscles. The epidermal growth factor (EGF) elicits cell responses by binding to the EGF receptor (EGFR). EGFR immunoreactivity was observed in the axon and lamellar cells of Meissner corpuscles as well as in the axon, inner core, outer core, and capsule of Pacinian corpuscles. On the other hand, neurotrophins (NGF, BDNF, NT-3, and NT-4/5) act on responsive nerve cells binding two types of receptors: p75LANTR (the low-affinity pan-neurotrophin receptor) and tyrosine-kinase receptors encoded by the trk family of proto-oncogenes (high-affinity signaling neurotrophin receptors). TrkA, TrkB, and TrkC proteins are the preferred receptors for NGF, BDNFINT-4/5, and NT-3, respectively. In developing and adult human mammalian skin, Meissner and Pacinian corpuscles display p75 and TrkA immunoreactivity, both being highly colocalized. BDNF and TrkB were found in the lamellar cells and the axon, respectively, in the Meissner and Pacinian corpuscles of developing and adult subjects. Interestingly both decreased with age ([25], Vega et al., unpublished]). Classical neuropeptides were detected in the human cutaneous sensory corpuscles, too. Meissner corpuscles display immunoreactivity for substance P IR, neuropeptide Y, and neurokinin A. Epithelial membrane antigen (EMA) and glucose-transporter 1 (Glut-1) are present in the cells of the outer core and Pacinian corpuscles. Leucocytary-7 antigen, a myelin- associated glycoprotein, was found in the inner core cells of some Pacinian corpuscles, and myelin basic protein was detected in around 25% of Meissner corpuscles as well as in the preterminal segment of Pacinian corpuscles. Mechanically gated ion channels are at the basis of mechanotransduction and occur along the somatosensory neurons that reach the skin, including the peripheral extreme tip that forms sensory corpuscles. Moreover, these channels can also be present in periaxonic cells. Thus, deformations in the membrane differ in the cells that form the mechanorecep- tors (i.e., axon, glial cells, and endoneurial and/or perineurial fibroblast) and trigger the opening of mechanosensitive ion channels that transduce mechanical energy into electrical activity. The axon of Meissner and Pacinian corpuscles display acid-sensing ion channel 2 (ASIC2), transient receptor potential vanilloid 4 (TRPV4), transient receptor potential canonical 6 (TRPC6), and PIEZO2 immunoreactivity, whereas the inner core of the Pacinian and the lamellar cells of Meissner occasionally show ASIC2 and 4 TRPV4 [37,38]. The extracellular matrix of cutaneous sensory corpuscles is a complex arrangement of molecules filling the spaces between cells, which consist of fibrillary proteins such as colla- gens and fibronectins and glycosaminoglycans. A major differentiation of the extracellular matrix is the basal lamina, and two main components of it, laminin and type IV collagen, have been detected in human Meisner and Pacinian corpuscles. Interestingly, heparan sul- fate proteoglycans were colocalized with type IV collagen in Meissner corpuscles and were J. Clin. Med. 2021, 10, 227 10 of 12

located in the outer core lamellae and capsule, but not in the inner core or the intermediate layer, in Pacinian corpuscles [18]. Chondroitin sulfate was observed in the intermediate layer of Pacinian corpuscles but was never colocalized with heparan sulfate proteoglycans and was absent from Meissner corpuscles [16]. On the other hand, the distribution of class I and class II small leucine-rich proteoglycans in human cutaneous Pacinian corpuscles was as follows: the inner core expressed decorin, biglycan, lumican, fibromodulin, and osteoadherin; the intermediate layer displayed immunoreactivity for osteoadherin; the outer core expressed biglycan, decorin, lumican, fibromodulin, and osteoadherin; and the capsule contained biglycan, decorin, fibromodulin, and lumican. Asporin, prolargin, and keratocan were undetectable [17].

7. Clinical and Pathological Interest of Cutaneous Sensory Corpuscles and Concluding Remarks Sensory corpuscles represent the most superficial part of the peripheral nervous system in vertebrates and are therefore easily accessible to be studied. A simple skin biopsy consents the obtention of material to analyze not only the morphology but also the protein composition of the sensory corpuscles, especially the corpuscles of Meissner. In Figures4 and6, and illustrating this review, actual knowledge about the proteins identified in the different cell types and the extracellular matrix of human cutaneous sensory corpuscles are included. Meissner corpuscles survive denervation for even more than 10 years, but denervated laminar cells lack some antigens and change the expression pattern of some others. They also change in morphology and antigen expression after nerve section or entrapment and spinal cord lesion. In recent years, Meissner corpuscles have gained interest since they are absent or reduced in some pathologies involving the peripheral nervous system such as diabetes and HIV-positive patients. In addition, a marked reduction in the number of Meissner corpuscles has been reported in patients with Charcot–Marie–Tooth disease. In multiple sclerosis, axonal degeneration occurs, which reduces the density and structural characteristic density of Meissner corpuscles. Similar findings are found in POEMS syn- drome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). In some diseases of the central nervous system, abnormalities have also been reported in Meissner corpuscles; for example, a reduction in Meissner corpuscle density in Parkinson’s disease. Reductions in the number of Meissner corpuscles have been reported in spinobulbar muscular atrophy, in Friedreich ataxia, and some psychiatric arteries [19,20]. Pacinian corpuscles in adult subjects survive denervation, showing no structural nor immunohistochemical changes [39]. Tumors involving Pacinian corpuscles are rare and have been defined as (or hyperplasia) and neurofibroma [40], which are occasionally painful [41]. Hyperplasia and hypertrophy of Pacinian corpuscles adjacent to digital nerves have been reported, although they are very rare [42–45]. Therefore, and as a summary, the knowledge of the distribution, morphological characteristics, protein composition, and age-dependent changes in cutaneous sensory corpuscles is of utmost interest to pathologists and dermatologists with a view to using their analysis in the diagnosis and monitoring of treatments.

Author Contributions: Conceptualization, R.C. and J.A.V.; methodology, R.C. and J.G.-P.; software, J.G.-P.; validation, R.C. and J.G.-P.; formal analysis, J.A.V.; investigation, R.C. and J.G.-P.; resources, J.C.; data curation, J.G.-P.; writing—original draft preparation, R.C., J.A.V.; writing—review and editing, J.C. and J.A.V.; visualization, R.C. and J.G.-P.; supervision, J.A.V.; project administration, J.C.; funding acquisition, J.C. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. J. Clin. Med. 2021, 10, 227 11 of 12

Data Availability Statement: Data supporting the images of this Review will be available from the corresponding author upon reasonable request. Acknowledgments: The authors thank Luis Aulló for preparing the drawings that illustrate the paper. Conflicts of Interest: The authors declare no conflict of interest.

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