The skin of primates. XXXIV. The skin of the golden spider monkey (Ateles geoffroyi)

The skin of the golden spider monkey (Ateles geoffroyi) has many histological and histochemical similarities to that of the woolly monkey (Lagothrix lagotricha) and howler monkey (Alouatta caraya); however, this monkey possesses certain peculiar properties such as large sebaceous glands, a combined distributional pattern of eccrine and apocrine sweat glands, and abundant alkaline phosphatase in the sebaceous glands, apocrine and eccrine sweat glands. In brief, the anatomical and histochemical properties of the skin of this animal are more similar to those of the howler monkey than to the woolly monkey. In addition, the skin of these three Ceboids falls phylogenetically between that of the Cercopithecoidea and Pithecoidea.     

The skin of primates. XXXVII. The skin of the pig-tail macaque (Macaca nemestrina)

The skin of the pig-tail macaque is basically similar to that of the rhesus monkey and the stump-tail macaque. The epidermis is thin and contains occasional basal melanocytes. The dermis, rich in elastic fibers, is practically free of pigment-containing cells. The upper dermis is highly vascular in the perianal region and sex skin. Cholinesterase-reactive nerve endings are plentiful beneath the friction surfaces of the pes and manus, mucous membranes, and junction of the hairy gluteus and glabrous ischial callosity. Hederiform-like endings are present in the eyelid, pinna, and frontal scalp. Apocrine and eccrine sweat glands occur throughout the hairy skin in a 2–3: 1 ratio. Both types are invested by nerves reactive for acetyl- and butyrylcholinesterase.     

Differential expression of dipeptidyl peptidase IV in human versus cynomolgus monkey skin eccrine sweat glands

Dipeptidyl peptidase IV (DPP4) is a peptidase whose inhibition is beneficial in Type II diabetes treatment. Several evidences suggest potential implication of DPP4 in skin disorders such as psoriasis, keloids and fibrotic skin diseases where its inhibition could also be beneficial. DPP4 expression in human skin was described mainly in dermal fibroblasts and a subset of keratinocytes in the basal layer. Of importance in the perspective of preclinical experimentation, DPP4 distribution in skin of non-human primate species has not been documented. This report evidences unexpected differences between a set of human and cynomolgus monkey skin samples revealing a major expression of DPP4 in eccrine sweat glands of cynomolgus monkeys but not in humans. This represents a unique distinctive feature compared to the conserved expression of dipeptidyl peptidases 8 and 9 and potential relevant DPP4 substrates such as neuropeptide Y (NPY) and receptors (NPY-receptor 1 and Neurokinin receptor). Finally the observation that cathepsin D, an unrelated protease, shows the opposite expression compared to DPP4 (present in human but not in cynomolgus monkey eccrine sweat glands) could indicate that human eccrine sweat glands evolved a divergent protease repertoire compared to non-human primates. These unexpected differences in the eccrine sweat glands protease repertoire will need to be confirmed extending the analysis to a major number of donors but could imply possible biochemical divergences, reflecting the functional evolution of the glands and the control of their activity. Our findings also demonstrate that non-human primates studies aiming at understanding DPP4 function in skin biology are not readily translatable to human.     

The skin of primates. XXXIX. The skin of the white-browed capuchin (Cebus albifrons)

The skin of the white-browed capuchin (Cebus albifrons), although basically similar to that of the squirrel monkey (Saimiri sciureus), contains several outstanding peculiarities: (1) both the epidermis and dermis of the general body surface are devoid of melanotic melanocytes; (2) the skin of the prehensile tail has no modified, glabrous friction surface; (3) the prehensile surface of the tail has no specialized nerve end-organs; (4) cholinesterase-positive, papillary nerve end-organs rest beneath the epidermal ridges of volar skin; and (5) both the clear cells and dark cells of the eccrine glands contain glycogen but neither shows phosphorylase activity.     

Primate models to study eccrine sweating

The histochemistry and histology of the eccrine sweat gland in the rhesus monkey (Macaca mulatta) are described. The histochemical distribution and localization of enzymes and substrates are very similar to those found in the human; innervation is cholinergic. Active eccrine glands on the general body surface average 136 glands/cm². Above the thermal neutral zone (TNZ), sweating is the major avenue for heat loss and the role of panting in dissipating heat is relatively insignificant. The intrahypothalamic administration of prostaglandin E₁ (PGE₁) suppresses sweating and leads to an increase in core temperature. A linear relation is found between local sweat rates on the general body surface and clamped hypothalamic temperature. Studies also provide direct support for the concept that brain temperature and skin temperature interact additively in the control of sweating in higher primates. The functional characteristics of eccrine sweating in the patas monkey (Erythocebus) are qualitatively similar to those in the rhesus monkey. The patas monkey maintains a relatively constant rectal temperature (37.6–38.4°C) when equilibrated to a wide range of ambient temperaures of 15–40°C. Eccrine sweating is the main effector system for heat dissipation above the TNZ. We emphasize here that evaporative heat loss that is due to sweating is related to both mean skin and mean body temperature and at 40°C is 40% higher than that recorded from the rhesus monkey. These results indicate that the patas monkey, because of its high sweating capacity and other similarities with the human eccrine system, is a most appropriate animal model for comparative studies of eccrine sweat gland function in primates in general.     

The skin of primates. 28. The stump-tail macaque (Macaca speciosa)

Though having some similarities to that of the rhesus monkey, the skin of the stump-tail macaque has several unique features. The epidermis has a sparse population of active melanocytes, and there is practically no pigmentation in the dermis. The dermis is rich in elastic fibers, the function of which seems to be to anchor the hair follicles and the arrectores pilorum muscles, and the superficial blood vessels. Large numbers of eccrine and apocrine sweat glands in the forehead and scalp are reminiscent of the axillary organ in the Hominioidea. The very large sebaceous glands on the face and bald forehead and scalp resemble those of man. The forehead and anterior portion of the scalp are bald in the adult but not in juvenile animals. In spite of an apparently rich pelage, these animals seem to show a trend toward nakedness.     

Three-dimensional reconstructed eccrine sweat glands with vascularization and cholinergic and adrenergic innervation

Functional integrity of the regenerated tissues requires not only structural integrity but also vascularization and innervation. We previously demonstrated that the three-dimensional (3D) reconstructed eccrine sweat glands had similar structures as those of the native ones did, but whether the 3D reconstructed glands possessing vascularization and innervation was still unknown. In the study, Matrigel-embedded eccrine sweat gland cells were implanted under the inguinal skin. Ten weeks post-implantation, the vascularization, and innervation in the 10-week reconstructed eccrine sweat glands and native human eccrine sweat glands were detected by immunofluorescence staining. The results showed that the fluorescent signals of general neuronal marker protein gene product 9.5, adrenergic nerve fiber marker tyrosine hydroxylase, and cholinergic nerve fiber markers acetylcholinesterase and vasoactive intestinal peptide embraced the 3D reconstructed glands in circular patterns, as the signals appeared in native eccrine sweat glands. There were many CD31- and von Willebrand factor-positive vessels growing into the plugs. We demonstrated that the 3D reconstructed eccrine sweat glands were nourished by blood vessels, and we for the first time demonstrated that the engineering sweat glands were innervated by both cholinergic and adrenergic fibers. In conclusion, the 3D reconstructed eccrine sweat glands may have functions as the native ones do.     

Localization of sex steroid receptors in human skin

Sex steroid hormones are involved in regulation of skin development and functions as well as in some skin pathological events. To determine the sites of action of estrogens, androgens and progestins, studies have been performed during the recent years to accurately localize receptors for each steroid hormone in human skin. Androgen receptors (AR) have been localized in most keratinocytes in epidermis. In the dermis, AR was detected in about 10% of fibroblasts. In sebaceous glands, AR was observed in both basal cells and sebocytes. In hair follicles, AR expression was restricted to dermal papillar cells. In eccrine sweat glands, only few secretory cells were observed to express AR. Estrogen receptor (ER) alpha was poorly expressing, being restricted to sebocytes. In contrast, ERbeta was found to be highly expressed in the epidermis, sebaceous glands (basal cells and sebocytes) and eccrine sweat glands. In the hair follicle, ERbeta is widely expressed with strong nuclear staining in dermal papilla cells, inner sheath cells, matrix cells and outer sheath cells including the buldge region. Progesterone receptors (PR) staining was found in nuclei of some keratinocytes and in nuclei of basal cells and sebocytes in sebaceous glands. PR nuclear staining was also observed in dermal papilla cells of hair follicles and in eccrine sweat glands. This information on the differential localization of sex steroid receptors in human skin should be of great help for future investigation on the specific role of each steroid on skin and its appendages.     

The skin of primates. XL. The skin of the cottontop pinché Saguinus (=Oedipomidas) oedipus

The skin of Saguinus (= Oedipomidas) oedipus Linnaeus, is basically similar to that of the red-mantled tamarin, Saguinus (= Tamarinus) fuscicollis Spix; it has several peculiarities: (1) a circumscribed tuft of vibrissae on the ulnar aspect of the wrist; (2) an accumulation of apocrine glands over the sternum; and (3) an extensive posterior abdominal field of gigantic sebaceous glands admixed with large apocrine glands, better developed in the female. The epidermis, dermis, hair follicles, sebaceous ducts, and apocrine excretory ducts are all heavily pigmented. Hairs are arranged in linear perfect sets; the epithelial sac of quiescent follicles is devoid of glycogen and phosphorylase. Eccrine sweat glands are restricted to the volar friction surfaces and contain no glycogen. Only the coiled excretory ducts of the eccrine glands contain phosphorylase. All cutaneous nerve fibers are more reactive for acetylthan butyrylcholinesterase.     

The evolution of sweat glands

Mammals have two kinds of sweat glands, apocrine and eccrine, which provide for thermal cooling. In this paper we describe the distribution and characteristics of these glands in selected mammals, especially primates, and reject the suggested development of the eccrine gland from the apocrine gland during the Tertiary geological period. The evidence strongly suggests that the two glands, depending on the presence or absence of fur, have equal and similar functions among mammals; apocrine glands are not primitive. However, there is a unique and remarkable thermal eccrine system in humans; we suggest that this system evolved in concert with bipedalism and a smooth hairless skin.Iowa Quaternary Studies Contribution No. 47     

Immunohistologic studies of the distribution of proliferative compartments in the appendages of adult human skin

Both, calmodulin (CaM) as well as the antigen Ki67 show a close relationship to cell proliferation. By means of specific antibodies against them, it has become possible to study the spatial distribution of proliferative compartments in tissues. We performed an indirect immunofluorescence study on unfixed frozen sections of human adult skin to gain more informations about the spatial distribution of immunoreactive CaM and Ki67 in skin appendages, i.e. anagen hair follicle, sebaceous and eccrine sweat gland. Two major patterns of immunoreactivity were seen: Type (1) or epidermis-like, which was present in the interfollicular epidermis and the pilosebaceous unit. Type (2) or sweat gland type, which was seen in eccrine sweat glands. Both types disclosed significant differences in the relative number of proliferative cells in S-phase, which might be a consequence of a quiet different tissue architecture. Furthermore, myoepithelial cells of secretory coils were likely to represent mainly SQ-cells. Their immunoreactivity in human skin was quiet different from other parts of eccrine sweat glands suggesting another ontogenetic pathway.     

Immunohistochemical localization of activated EGF receptor in human eccrine and apocrine sweat glands.

Epidermal growth factor (EGF) is secreted into sweat from secretory cells of human sweat glands. The function of EGF in sweat is poorly understood. The biological function of EGF is exerted by the binding of EGF to the receptor (EGFR) and its activation. Therefore, we immunohistochemically localized the activated form of EGFR in human eccrine and apocrine sweat glands to assess the functional importance of the EGF-EGFR system in human sweat glands. Frozen sections of human skin were stained with a monoclonal antibody (MAb) specific for tyrosine-phosphorylated (activated) EGFR and with an MAb that stains both activated and non-activated EGFR. In the secretory portion of eccrine sweat glands, nuclei of the secretory cells were stained with the anti-activated EGFR MAb. In coiled and straight portions of eccrine sweat ducts, nuclei of luminal and peripheral cells were stained with the antibody specific for activated EGFR. Luminal cell membranes and luminal cytoplasm of inner ductal cells possessed non-activated EGFR. In the secretory portion of apocrine sweat glands, activated EGFRs were present in cytoplasm and nuclei of secretory cells. These data suggest that EGF, already known to be present in the cytoplasm of secretory cells in eccrine and apocrine sweat glands, activates EGFR in the nuclei of secretory cells themselves in an intracrine manner. Because ductal cells do not express EGF, EGF in the sweat secreted from the secretory cells should activate EGFR in the ductal cells in a paracrine manner. (J Histochem Cytochem 49:597-601, 2001)     

A melanocyte–melanoma precursor niche in sweat glands of volar skin

Determination of the niche for early‐stage cancer remains a challenging issue. Melanoma is an aggressive cancer of the melanocyte lineage. Early melanoma cells are often found in the epidermis around sweat ducts of human volar skin, and the skin pigmentation pattern is an early diagnostic sign of acral melanoma. However, the niche for melanoma precursors has not been determined yet. Here, we report that the secretory portion (SP) of eccrine sweat glands provide an anatomical niche for melanocyte–melanoma precursor cells. Using lineage‐tagged H2B‐GFP reporter mice, we found that melanoblasts that colonize sweat glands during development are maintained in an immature, slow‐cycling state but renew themselves in response to genomic stress and provide their differentiating progeny to the epidermis. FISH analysis of human acral melanoma expanding in the epidermis revealed that unpigmented melanoblasts with significant cyclin D1 gene amplification reside deep in the SP of particular sweat gland(s). These findings indicate that sweat glands maintain melanocyte–melanoma precursors in an immature state in the niche and explain the preferential distribution of early melanoma cells around sweat glands in human volar skin.     

Thermogenic and psychogenic recruitment of human eccrine sweat glands: Variations between glabrous and non-glabrous skin surfaces

Human eccrine sweat-gland recruitment and secretion rates were investigated from the glabrous (volar) and non-glabrous hand surfaces during psychogenic (mental arithmetic) and thermogenic stimuli (mild hyperthermia). It was hypothesised that these treatments would activate glands from both skin surfaces, with the non-thermal stimulus increasing secretion rates primarily by recruiting more sweat glands. Ten healthy men participated in two seated, resting trials in temperate conditions (25–26 °C). Trials commenced under normothermic conditions during which the first psychogenic stress was applied. That was followed by passive heating (0.5 °C mean body temperature elevation) and thermal clamping, with a second cognitive challenge then applied. Sudomotor activity was evaluated from both hands, with colourimetry used to identify activated sweat glands, skin conductance to determine the onset of precursor sweating and ventilated sweat capsules to measure rates of discharged sweating. From glandular activation and sweat rate data, sweat-gland outputs were derived. These psychogenic and thermogenic stimuli activated sweat glands from both the glabrous and non-glabrous skin surfaces, with the former dominating at the glabrous skin and the latter at the non-glabrous surface. Indeed, those stimuli individually accounted for ~90% of the site-specific maximal number of activated sweat glands observed when both stimuli were simultaneously applied. During the normothermic psychological stimulation, sweating from the glabrous surface was elevated via a 185% increase in the number of activated glands within the first 60 s. The hypothetical mechanism for this response may involve the serial activation of additional eccrine sweat glands during the progressive evolution of psychogenic sweating.     

The skin of primates. XLI. The skin of the silver marmoset—Callithrix (= Mico) Argentata

The skin of the silver marmoset, Callithrix (= Mico) argentata Linnaeus, has many outstanding characteristics. The unusually thin epidermis and dermis are generally devoid of melanotic melanocytes. The surface of the interramal gular region is peppered with small, elevated papillae; that of the corpus penis is characterized by keratinized, proximally directed hollow spines in whose cavities are organized nerve end-organs and capillary loops. Cholinesterase-reactive papillary nerve end-organs and Meissner corpuscles populate all volar friction surfaces. A highly vascular dermis and subcutaneous fat pad partially contribute to the characteristic rubicund color of the face, external ears, and anogenital region. Many body surface hairs are accompanied by the classic Haarscheibe of Pinkus. Sinus hairs are plentiful; a circumscribed vibrissa-bearing eminence is located on the ventral ulnar aspect of each wrist. Alkaline phosphatase-positive, stellate-shaped cells are found on the outer root sheath and epithelial sac of active and quiescent hairs in all cephalic regions; such cells are not argyrophilic, aurophilic, or osmiophilic. Hairs grow in linear perfect sets of 3 to 5 follicles; they do not grow singly on the cheek. Large sebaceous glands contain alkaline phosphatase in their peripheral acini; extensive fields of gigantic multilobular sebaceous glands contribute to the distinct, opaque-white color of the scrotal skin. Numbers of apocrine sweat glands are diminished in cephalic regions but one gland occurs with each hair follicle in the axilla, scrotum, suprapubic region, and ulnar eminence. Relatively avascular eccrine sweat glands are confined to the volar friction surfaces. Their secretory coils contain sporadically distributed glycogen and phosphorylase and surrounding nerves are much more reactive for acetyl- than butyrylcholinesterase.     

The protease corin regulates electrolyte homeostasis in eccrine sweat glands

Sweating is a basic skin function in body temperature control. In sweat glands, salt excretion and reabsorption are regulated to avoid electrolyte imbalance. To date, the mechanism underlying such regulation is not fully understood. Corin is a transmembrane protease that activates atrial natriuretic peptide (ANP), a cardiac hormone essential for normal blood volume and pressure. Here, we report an unexpected role of corin in sweat glands to promote sweat and salt excretion in regulating electrolyte homeostasis. In human and mouse eccrine sweat glands, corin and ANP are expressed in the luminal epithelial cells. In corin-deficient mice on normal- and high-salt diets, sweat and salt excretion is reduced. This phenotype is associated with enhanced epithelial sodium channel (ENaC) activity that mediates Na⁺ and water reabsorption. Treatment of amiloride, an ENaC inhibitor, normalizes sweat and salt excretion in corin-deficient mice. Moreover, treatment of aldosterone decreases sweat and salt excretion in wild-type (WT), but not corin-deficient, mice. These results reveal an important regulatory function of corin in eccrine sweat glands to promote sweat and salt excretion.

Sweating is a basic skin function in body temperature control, and salt excretion and reabsorption in sweat glands are essential for salt-water balance. This study identifies corin, a transmembrane protease that activates atrial natriuretic peptide, as a key enzyme in regulating salt excretion in the skin.     

Peripheral choline acetyltransferase in rat skin demonstrated by immunohistochemistry

Conventional choline acetyltransferase immunohistochemistry has been used widely for visualizing central cholinergic neurons and fibers but not often for labeling peripheral structures, probably because of their poor staining. The recent identification of the peripheral type of choline acetyltransferase (pChAT) has enabled the clear immunohistochemical detection of many known peripheral cholinergic elements. Here, we report the presence of pChAT-immunoreactive nerve fibers in rat skin. Intensely stained nerve fibers were distributed in association with eccrine sweat glands, blood vessels, hair follicles and portions just beneath the epidermis. These results suggest that pChAT-positive nerves participate in the sympathetic cholinergic innervation of eccrine sweat glands. Moreover, pChAT also appears to play a role in cutaneous sensory nerve endings. These findings are supported by the presence of many pChAT-positive neuronal cells in the sympathetic ganglion and dorsal root ganglion. Thus, pChAT immunohistochemistry should provide a novel and unique tool for studying cholinergic nerves in the skin.     

Skin penetration of infective hookworm larvae. II. The path of migration of infective larvae of Ancylostoma braziliense in the metacarpal foot pads of dogs

The hairless metacarpal foot pads of six hookworm-free puppies were exposed to infective larvae of Ancylostoma braziliense. Serial sections of the biopts stained with Harris' haematoxylin and eosin showed that the infective larvae are able to penetrate the toughest region of canine skin. Pores of eccrine sweat glands did not seem to constitute sites of entry and no larvae were detected in these glands. Larvae were only observed in the epidermis. The histopathology of the infected skin of the foot pads of the puppies was similar to that in human skin with "creeping eruption" as described by Fülleborn (1927). The biopts appeared to consist of hairy skin as well. In the unexposed adjacent hairy skin of the foot pads, larvae were also observed. They were found in the epidermis, hair follicle systems and dermis, suggesting that the migration from the epidermis into deeper tissue depends on the presence of the hair follicle systems.     

Time course of differentiation of different cell types in 3D-reconstructed eccrine sweat glands

Epidermal basal cells invaginate into the dermis to form sweat ducts, which then grow downwards further to form secretory coils during the ontogenesis of eccrine sweat glands, but the time course of differentiation of different cell types in 3D-reconstructed eccrine sweat glands remain unclear. In this study, secretory cell-specific marker K7, clear secretory cell-specific marker CA II, dark secretory cell-specific marker GCDFP-15, myoepithelial cell-specific marker α-SMA, inner duct cell-specific marker S100P and outer duct cell-specific marker S100A2 were detected by immunofluorescence staining. The results showed that S100P and S100A2 were first detected at 2 weeks post implantation, K7 and α-SMA at 3 weeks, and GCDFP-15 and CA II at 4 weeks. The differentiation of ducts preceded secretory coils in 3D-reconstructed eccrine sweat glands. After 8 weeks post implantation, the distribution of these markers in 3D-reconstructed eccrine sweat glands was similar to that in native ones, and the percentage of the 3D-reconstructed glands expressing these markers maintained steady. We conclude that although the 3D-reconstructed and native eccrine sweat glands originated from different cells, the differentiation of different cell types in 3D-reconstructed eccrine sweat glands parallels the sequence observed during embryonic development.     

The metabolism and hormonal responses of human eccrine sweat glands isolated by collagenase digestion.

1. Collagenase digestion of biopsies of human skin yields eccrine sweat glands that can be picked out under binocular light microscopy. The glands are viable as determined by the exclusion of Trypan Blue, the uptake of Methylene Blue, electron microscopy, the rate of lactate dehydrogenase release, ATP content and the rates of glucose oxidation and lactate release. 2. It is proposed that eccrine sweat glands engage in aerobic glycolysis, which accounts for the high content of lactate in sweat (15--60 mM) and the high lactate/pyruvate ratio (100: 1) [Emrich & Zwiebel (1966) Pfluegers Arch. 290, 315--319]. 3. Acetylcholine causes a 4-fold increase in cyclic GMP content, dilatation of the intercellular canaliculi and a reversible, atropine-sensitive, 2-fold increase in the rates of glucose oxidation and lactate release. 4. Isoprenaline causes a 2.5-fold increase in cyclic AMP content. Phenylephrine does not significantly alter cyclic nucleotide metabolism.