Intraepidermal nerve-fibre density as a biomarker of the course of neuropathy in patients with Type 2 diabetes mellitus.

AIMS: This paper aims to investigate whether intraepidermal nerve-fibre density (IENFD) may be used as a marker of the course of neuropathy in patients with Type 2 diabetes mellitus. METHODS: Skin biopsies from the distal leg were serially evaluated in a group of 30 patients with Type 2 diabetes mellitus (median age 60 years, 17 men) with a short duration of diabetes (< 3 years) and good glucose control, and in 23 age- and sex-matched controls. The time intervals between biopsies were > 2 years (median 33.8 months). Eighteen patients with Type 2 diabetes mellitus had symptoms or signs of distal symmetrical diabetic polyneuropathy, 12 had no neuropathy. RESULTS: At first skin biopsy, IENFD was normal in all controls and in patients without neuropathy (mean 9.5 and 7.9 fibres/mm, respectively) compared with abnormal IENFD in 77.8% in patients with polyneuropathy (mean 3.4 fibres/mm). The annual rate of intraepidermal nerve-fibre (IENF) loss expressed as a percentage of the first IENFD value in patients with diabetic polyneuropathy was significantly higher [mean (se), 11.95 (3.82)%] compared with controls [1.92 (1.81)%, P < 0.001] and similar to patients without polyneuropathy [12.16 (4.38)%]. The rate of IENF loss did not correlate with degree of glucose control. CONCLUSIONS: The annual rate of IENF loss in patients with Type 2 diabetes mellitus was several times higher than that of healthy participants, irrespective of the presence of signs or symptoms of diabetic polyneuropathy at initial evaluation. The change in IENFD is not linear and should be expressed as a proportion of initial IENFD to serve as a marker of the course of diabetic neuropathy.

Increased invasion of ED-1 positive macrophages in both ipsi- and contralateral dorsal root ganglia following unilateral nerve injuries.

There is an increasing evidence that unilateral nerve injury induces cellular and molecular changes in the associated DRG not only on the ipsilateral but also in the contralateral side. In this investigation, ED-1+ macrophages were quantified by image analysis in the naïve L5 DRG (nDRG) and compared with the ipsi- and contralateral ones 2 and 4 weeks after unilateral sciatic nerve ligature and ventral root transection (VRT). A few ED-1+ macrophages were found in nDRG but not closely associated with the neuronal bodies. In contrast, following nerve injuries ED-1+ macrophages and their processes were frequently located close neuronal bodies and became their satellite cells. Moreover, an increased number of ED-1+ cells was found in the ipsilateral DRG 2 weeks after unilateral sciatic nerve ligature or VRT, but no significant differences were measured between 2 and 4 weeks after both types of nerve lesion. Contralateral DRG displayed a significant enhanced number of ED-1+ cells no sooner than 4 weeks from sciatic nerve ligature. In contrast, VRT induced a significant increased invasion of the ED-1+ cells in the contralateral DRG as early as 2 weeks after operation. Our experiments indicate that a significantly higher number of ED-1+ macrophages remained in both ipsi- and contralateral DRG up to 4 weeks from nerve injury. Based on results from different models of nerve injury, we suggest that more than one mechanism operates to stimulate the invasion of ED-1+ macrophages into the DRG including retrograde transport of factors produced during Wallerian degeneration or their delivery by blood flow. Signaling for macrophage invasion into DRG contralateral to nerve injury may be mediated by lost motoneurons or by interneurones.

Local chemical sympathectomy of rat bone marrow and its effect on marrow cell composition.

Existing experimental studies of the effect of sympathetic nerve fibers on bone marrow cells are based on the systemic administration of neurotoxic 6-hydroxydopamine. The method of global chemical sympathectomy has some serious disadvantages and could lead to questionable results. We describe a new method of local chemical sympathectomy of rat femoral bone marrow using guanethidine (Ismelin) delivery using an osmotic mini pump. Local guanethidine treatment for 14days led to complete elimination of sympathetic fibers in femoral bone marrow in contrast to bone marrow of contralateral or naïve femurs. Ablation of sympathetic fibers was associated with a loss of rat endothelial cell marker (RECA) indicating immunophenotype changes in blood vessel endothelial cells, but no significant effect of guanethidine was found on the survival of endothelial cells and mesenchymal stem cells in vitro. Moreover, local guanethidine treatment also elicited a significant reduction of Nestin+/SDF1+ mesenchymal stem cells and c-Kit+/CD90+ hematopoietic stem cells in femoral bone marrow. Tissue-specific chemical sympathectomy of rat bone marrow by guanethidine overcomes some of the drawbacks of systemic administration of neurotoxic compounds like 6-hydroxydopamine and delivers unequivocal evidence on the effects of sympathetic innervation on the cell content of bone marrow.

Enzyme histochemistry of cutaneous sensory nerve formations.

The cutaneous sensory nerve formations belong to the structures which are studied intensely by the enzyme activity histochemistry since the early history of this technique. The histochemical localization of the activities of nonspecific cholinesterase, alkaline phosphatases, acid phosphatase, adenosine tri- and diphosphatases, adenylate cyclase, and dipeptidylpeptidase-IV in the cutaneous sensory nerve formations, mainly sensory corpuscles, is reviewed. The histochemical approach has brought new knowledge of both morphological building of these unique structures and their biochemical constituents. Taken together, the present results of enzyme histochemistry provide insight into the function of enzymes, and disclose new relationships between the sensory terminals and auxiliary structures in the cutaneous sensory nerve formations.

Degeneration and regeneration of cutaneous sensory nerve formations.

Auxiliary structures of the cutaneous sensory nerve formations (SNF) are dependent on sensory innervation during their critical period of development. Denervation of mature cutaneous corpuscles results in survival of the terminal Schwann cells and the capsular structures which are probably responsible for successful reinnervation of the cutaneous SNF. In addition, the basal lamina tubes of Schwann cells are connected with the terminal Schwann cells and play an important role in the guidance of regrowing axons to their original targets. Long-lasting denervation causes atrophic changes of the terminal Schwann cells and alterations of their molecular equipment. These atrophic changes in the terminal Schwann cells may be responsible for erroneous reinnervation of cutaneous SNF. A population of the cutaneous Merkel cells surviving denervation may also serve as targets for regrowing sensory axons. The basal laminae of terminal Schwann cells are produced under control of the sensory terminals during maturation of cutaneous SNF. In adult animals, the basal laminae are capable of stimulating differentiation of migrated Schwann cells to the terminal Schwann cells without the presence of the sensory terminals. Nonspecific cholinesterase (nChE) is secreted by the terminal Schwann cells and is attached to their extracellular matrix. The synthesis of these molecules in adult animals is not influenced by the sensory terminals. However, the presence of nChE molecules is associated with living terminal Schwann cells. Fetal orthotopically grafted dorsal root ganglion (DRG) neurons have the ability to reinnervate cutaneous SNF of adult hosts. When cutaneous areas are denervated, axons from adjacent sensory nerves may extend collateral branches into this area. The capacity for such extension is dependent on: (1) type of sensory nerve ending, C and A delta fibers having significantly greater capacity than sensory axons of larger caliber; (2) age of the animal, immature animals generally showing a greater capacity for collateral sprouting; (3) the state of the adjacent axons, those already in a growth mode being more capable than "resting" ones; and (4) the regional and mechanical conditions at the site of denervation, hindpaw skin being much less extensively reinnervated by collateral fibers than that of the trunk.

Growth-associated protein (GAP-43) in terminal Schwann cells of rat Pacinian corpuscles.

Growth-associated protein (GAP-43) immunoreactivity was examined in Pacinian corpuscles of intact neonatal and adult rats as well as after denervation and reinnervation in adult rats. All immature Pacinian corpuscles were GAP-43 immunoreactive (GAP-43+) in their inner cores while only 46 +/- 5.6% of the mature corpuscles exhibited GAP-43+ inner cores. The frequency of GAP-43+ inner cores increased to 90 +/- 7.2% after their permanent denervation. The expression of GAP-43 in the inner cores was reduced by contact with regrowing axons, but 38 +/- 5.3% of Pacinian corpuscles retained GAP-43+ in their inner cores following reinnervation. These results indicate that GAP-43 regulation is not confined only to axons but also involves some extra-axonal cues, and support a role for this protein in the process formation by terminal Schwann cells.

Dipeptidylpeptidase IV activity in Meissner corpuscles of rhesus monkey and its possible function.

Histochemical investigation by means of light and electron microscopy revealed the presence of dipeptidylpeptidase IV activity in Meissner corpuscles of macaque glabrous skin. The enzyme activity was found in fibroblast-like cells forming an incomplete capsule around the Meissner corpuscle. Distinct electron-dense reaction product due to dipeptidylpeptidase IV activity was consistently localized in the plasma membrane of specialized Schwann cells enveloping the unmyelinated portion of sensory axons. Their axolemma was devoid of dipeptidylpeptidase IV reaction product. The membrane-bound dipeptidylpeptidase IV activity presented here and the occurrence of substance P-containing nerve fibers in primate Meissner corpuscles referred to elsewhere, suggest the possible functional involvement of the enzyme in the production of substance P fragments, influenced in different ways by the axon proper and its surrounding Schwann cells.

Non-specific cholinesterase activity of the developing peripheral nerves and its possible function in cells in intimate contact with growing axons of chick embryo.

The results presented here demonstrate non-specific cholinesterase (nChE) activity in the developing peripheral nerves of chick embryos at stages 25-26 according to Hamburger and Hamilton (1951, J. Morphol. 88, 49-92). Under the light microscope the use of simultaneous staining for nChE activity and silver proteinate impregnation revealed the axons to be surrounded by cells exhibiting nChE activity in the main nerve trunks and in the growing tips of nerves. Nerve branches arising from the main nerve trunks contained cells with positive reaction for nChE activity, too. Electron-dense particles of the reaction product indicating nChE activity were found in the rough endoplasmic reticulum and in the perinuclear envelope of cells in close contact with growing nerve fibers and their growth cones. The same distribution of nChE activity was found in cells which were located near to nerve fasciculi but without direct contact with axons. Surprisingly, the cells in close contact with axons and their growth cones exhibited the end product of nChE activity in the outer part of their plasma membrane. The cells enveloping axons within the nerve trunks were apparently Schwann cells, while those around the growth cones at nerve tips could be identified as Schwann cells and/or mesenchymal cells of the hindlimb. The nChE reaction product was also detected in the axolemma of nerve fibers and their growth cones. The distribution of nChE activity in the developing peripheral nerves of chick embryos suggests that these molecules may influence the process of axonal elongation and locomotion. Several possible mechanisms of nChE action on growing axons can be presumed: (i) intracellular Ca2+ level regulation; (ii) providing an adhesive substrate; and (iii) butyrate production affecting the cell metabolism and the distribution of neurotubules and neurofilaments. It is also assumed that nChE molecules are involved in the interactions of nerve fibers with Schwann cells and/or mesenchymal cells as well as in interneuronal interactions.

Restoration of lamellar structures in adult rat Pacinian corpuscles following their simultaneous freezing injury and denervation.

The capsule and inner core are multilamellar auxiliary structures enveloping the axon terminal of the Pacinian corpuscle. The freezing injury of the rat interosseal Pacinian corpuscles induced the destruction of all cellular components while the extracellular matrix including the basal laminae survive the treatment. Simultaneous denervation and the freezing treatment of the Pacinian corpuscles discovered an ability of the basal lamina and other components of the extracellular matrix to stimulate a differentiation of migrated Schwann cells and fibroblasts into multilamellar auxiliary structures. The restoration of inner core and capsule in the Pacinian corpuscles was independent of the presence of sensory axon terminals. The restored lamellar structures of Pacinian corpuscles in long-term surviving rat (4 to 8 months) displayed atrophic changes. The results suggest that the extracellular matrix of rat Pacinian corpuscles may contain molecules that are produced by Schwann cells and fibroblasts during maturation of the multilamellar auxiliary structures. The molecules deposited into the extracellular matrix are able to influence the redifferentiation of multilamellar auxiliary structures from immature cells.

The extracellular matrix of rat pacinian corpuscles: an analysis of its fine structure.

The Pacinian corpuscle consists of a sensory axon terminal that is enveloped by two different structures, the inner core and the capsule. Since proteoglycans are extremely water soluble and are extracted by conventional methods for electron microscopy, the current picture of the structural composition of the extracellular matrix in the inner core and the capsule of the Pacinian corpuscle is incomplete. To study the structural composition of the extracellular matrix of the Pacinian corpuscles, cationic dyes (ruthenium red, alcian blue, acridine orange) and tannic acid were applied simultaneously with the aldehyde fixation. The interosseal Pacinian corpuscles of the rat were fixed either in 2% formaldehyde and 1.5% glutaraldehyde, with the addition of one of these cationic dyes or, in Zamboni's fixative, with tannic acid added. The cationic dyes and tannic acid revealed a different structural pattern of proteoglycans in the extracellular matrix in the inner core and in the capsule of the rat Pacinian corpuscles. The inner core surrounding the sensory axon terminal is a compartment containing proteoglycans that were distributed not only in the extracellular matrix but also in the cytoplasm of the lamellae. In addition, this excitable domain was separated from the capsular fluid by a thick layer of proteoglycans on its surface. An enlarged interlamellar space of the capsule contained large amounts of proteoglycans that were removed by digestion with chondroitinase-ABC. Ruthenium red and alcian blue provided only electron dense granules, probably corresponding to collapsed monomeric proteoglycan molecules. Acridine orange and tannic acid preserved proteoglycans very well and made it possible to visualize them as "bottlebrush" structures in the electron microscope. These results show that the inner core and the capsule of rat Pacinian corpuscles have different structural patterns of proteoglycans, which are probably involved in different functions.

Regeneration of tactile lamellar corpuscles of the rat after postnatal freeze injury.

Tactile lamellar corpuscles were studied after freeze injury of rat toe pads under normal conditions and following permanent denervation in 1- to 65-day-old animals. In the innervated skin, digital corpuscles redifferentiated in all age groups examined during development and maturation. Characteristic of the reinnervated skin was a great diversity in the shape and size of newly formed corpuscles. Small corpuscles with only 1-3 lamellae around their terminals and well-developed corpuscles of about normal size with up to 15 lamellae were sometimes found within the same sample of skin. The regenerated corpuscles were reduced in number; they reappeared in only 50% of dermal papillae in the toe pads after freeze injury in 7-week-old rats, compared with approximately 100% of dermal papillae that contained lamellar corpuscles in normal toe-pad skin. In denervated toes, occasional corpuscular lamellar structures appeared first after freeze injury applied to 34-day-old rats. In the toe pads denervated and injured by freezing in 42- and 49-day-old rats, lamellar structures redifferentiated in about 10% of the papillae, and in 23.5% after freeze injury applied to 2-month-old rats. Unsatisfactory preservation of basal laminae at the former sites of the corpuscles and in the acellular peripheral nerve stumps, and/or insufficient migration of Schwann cells, may be responsible for the absence or abortive regeneration of lamellar structures in denervated skin of food pads after freeze injury in young rats.

A histochemical study by light and electron microscopy of the distribution of dipeptidyl peptidase-IV activity in the human dental pulp.

This activity was demonstrated in blood vessels, fibroblast-like cells, odontoblasts and Schwann cells surrounding non-myelinated axons. It was present on both the luminal and abluminal plasma membrane of endothelial cells. The plasma membrane of fibroblast-like cells and their processes had patches of fine electron-dense end-product corresponding to DPP-IV activity, while the plasma membrane of odontoblasts was loaded with a consistent reaction product. DPP-IV activity in the non-myelin-forming Schwann cells was in the plasma membrane of the free surface in contact with the extracellular matrix as well as in the plasma membrane in close contact with the axolemma. The plasma membrane of Schwann cells producing myelin sheath had no positive reaction for DPP-IV. The DPP-IV activity in the plasma membrane of fibroblast-like cells and odontoblasts may be associated with fibronectin-mediated adhesion to collagen, whereas the membrane-bound DPP-IV activity in endothelium and non-myelin-forming Schwann cells may be involved in cleavage of neuropeptides of other biologically active peptides.

A study of the dipeptidylpeptidase IV activity in cat fungiform papillae: light and electron microscope histochemistry.

The present paper describes histochemical study of the dipeptidylpeptidase IV activity in the nerve structures of cat fungiform papillae at the light and electron microscope levels. The dipeptidylpeptidase IV activity was found in blood vessels and nerve bundles entering the connective tissue stroma of fungiform papillae. The taste buds exhibited a moderate staining for the dipeptidylpeptidase IV activity. Ultracytochemical findings revealed this enzyme as membrane-bound in the endothelium of blood vessels, in plasma membrane of the Schwann cells at the axon-Schwann cell interface as well as in the taste bud cells. A possible function of the dipeptidylpeptidase IV activity in the peripheral nerve structures is discussed in view of the ability of this enzyme to cleave the substance P to the minor fragments with inherent physiological roles.

Electron microscopical study of non-specific cholinesterase activity in simple lamellar corpuscles of glabrous skin from cat rhinarium: a histochemical evidence for the presence of collagenase-sensitive molecular forms and their secretion.

The distribution of nCHE activity was studied histochemically in simple lamellar corpuscles (SLCs) of glabrous skin from cat rhinarium. The Schwann cells forming myelin sheaths in preterminal part of SCLs exhibited no positive reaction for nCHE activity. Prevalent reaction product was localized extracellularly in the inne core enveloping terminal portion of unmyelinated sensory axon. A dot-like shaped reaction product was deposited in the basal lamina of the inner core cells and their cytoplasmic lamellae or was scattered in enlarged interlamellar spaces. Only small amount of fine end product was found to be associated with the plasma membrane of inner core lamellae. Fine reaction product for nCHE activity was consistently localized in perinuclear and rER cisternae and saccules of the Golgi apparatus of inner core cells. Some vesicles around rER and the Golgi apparatus, ones beneath the plasma membrane, and tubular-like cisternal profiles oriented towards the surface contained nCHE end product, as well. The intracellular and extracellular localization of nCHE reaction product suggests that this enzyme behaves in cat SLCs as a secreted rather than as an integral membrane protein. A large amount of dot-like reaction product in the interlamellar spaces disappeared if the skin sections were treated with collagenase before incubation in the medium for histochemical detection of nCHE activity. The decrease of nCHE end product in SLCs of the skin sections after collagenase digestion was corroborated by means of light microdensitometer and electrometrical measurement. The histochemical detection and electrometrical measurement revealed that the majority of the reaction product in the interlamellar spaces of inner core corresponds with the nCHE molecules sensitive to collagenase treatment and they are probably counted among asymmetrical molecular forms.

Electron microscopical localization of non-specific cholinesterase activity in three principal parts of cat Pacinian corpuscles.

Non-specific cholinesterase (nCHE) activity was demonstrated histochemically on electron microscope level in 3 parts of Pacinian corpuscles from the cat mesenterium. The reaction product was abundant on the plasmic membrane of the inner core lamellae. Schwann cells of a myelinated portion of a sensory axon in Pacinian corpuscles were devoid of positive reaction to nCHE activity. These results are in agreement with those obtained in other sensory nerve endings. Therefore, the cells investing the terminal portion of an unmyelinated sensory axon are considered to be specialized Schwann cells. Furthermore, the amount of end product was lower on the specialized Schwann cells around ultraterminal than terminal portion of a sensory axon. A significantly higher nCHE activity confined to the inner core around the terminal portion of a sensory axon suggests the participation of this enzyme in the maintenance of ionic milieu in periaxonal microenvironment.

Ultrastructural localization of non-specific cholinesterase activity in rat muscle spindles.

Electron microscopical localization of non-specific cholinesterase activity was studied in the encapsulated part of rat hindlimb muscle spindles. After incubation of the muscle tissue in a medium containing butyrylthiocholine bromide as substrate and BW284c51 as the specific inhibitor of acetylcholinesterase, a distinct electron-dense precipitate corresponding to non-specific cholinesterase activity was found along the whole length of muscle spindles. The richest source of non-specific cholinesterase activity were the motor end-plates present in the polar and juxtaequatorial regions. Much smaller amounts of reaction deposits were found at the secondary sensory terminals in the juxtaequatorial zones. The primary sensory terminals in the equatorial zone contained only low amounts of the reaction product. A fine homogeneous reaction product was localized in the narrow spaces between Schwann cell processes or in gaps between the Schwann cell, and axonal and muscle membranes. A granular precipitate was localized on the basal lamina in the synapse region of motor terminals or covering Schwann cell processes and sensory terminals with adjacent intrafusal muscle fibres. Our results suggest that most of non-specific cholinesterase in muscle spindles is synthesized by the Schwann cells; but a small amount can also be synthesized by fibroblast-like cells forming the inner capsule of muscle spindles. Non-specific cholinesterase thus coexists with acetylcholinesterase at motor end-plates, but is single at sensory terminals. The function of non-specific cholinesterase in sensory receptors is still not clear. It seems most probable that non-specific cholinesterase in muscle spindles may play a role in the maintenance of the external milieu around nerve endings, especially in the sensory region.

Fine structural localization of non-specific cholinesterase activity in rat tendon organs.

Electron microscopical localization of non-specific cholinesterase (nChE) activity was studied in tendon organs of the rat hindlimb muscles. The comparison between neurotendinous part (with high nChE activity) and purely collagenous compartment(s) (with very low nChE activity) demonstrated that Schwann cells are the fundamental source of this enzyme in rat tendon organs. Although particles of the nChE reaction product were also found in and around fibroblasts in both neurotendinous and purely collagenous compartments, their contribution to the overall nChE was not significant. nChE activity in rat tendon organs displayed heterogeneity along the Ib sensory axon; the highest activity was related to the Schwann cell investment of the unmyelinated part of Ib axon, lower activity to sensory terminals covered only by basement membrane and negligible activity to the myelinated part of sensory axons. Particles of the non-specific cholinesterase reaction product persisted in the basement membrane of Schwann cells 20 d after degeneration of Ib sensory axons and their terminals. The function of non-specific cholinesterase in sensory receptors is still not clear. It is suggested that this enzyme may be involved in the maintenance of the ionic milieu around sensory axon terminals during or after functional activity.

The electron microscopic localization of alkaline phosphatase in Pacinian corpuscles of the cat.

The ultrastructural localization of alkaline phosphatase has been studied in Pacinian corpuscles of the cat mesentery by the method of Mayahara et al. (1967) with 3 substrates. As control studies, specimens were incubated in the medium containing L-cysteine (10 mmol) or EDTA (5 mmol). The electron opaque final reaction product was observed on plasmic membranes and in cytoplasm and pinocytotic vesicles of the inner core cells. The precipitate was present also in rough endoplasmic reticulum, multivesicular bodies, and cytoplasmic vacuoles of the inner core lamellae. The axon revealed the positive enzymatic activity in the axolemma and the scattered precipitate was found in axoplasm. The pinocytotic vesicles in the capillary endothelium entering Pacinian corpuscles contained the reaction product, too. The capsule lamellae were devoid of precipitate. Localization of alkaline phosphatase in pinocytotic vesicles of the inner core lamellae and capillary wall support the opinion that this enzyme plays the significant role in the phenomenon of the transport of molecules through inner core lamellae from capillaries to the axon in Pacinian corpuscles.

An immunocytochemical analysis of growing axons in a silicone chamber prefilled with artificial sponge matrix.

We have used antibodies against growth associated protein (GAP-43), phosphorylated neurofilament protein of 200 kDa molecular weight (RT-97) and substance P (SP) to analyze regrowing axons and their features in a silicone chamber filled with resorbable sponge matrix within the first two weeks after sciatic nerve transection in the rat. Growing axons identified with the GAP-43 antibody extended over a distance of about 7 mm from the proximal stump at 7 days and grew over a 10 mm gap within, 14 days. This is a markedly longer distance than in the case of the standard chamber model without artificial sponge matrix. The regrowing axons were labelled with RT-97 already on the 7th day up to a distance of 5 mm and they made up about 75% of all axons in the first segments. The number of RT-97-positive axons did not increase significantly over the next 7 days, although they could be identified over a longer distance. Some of the growing axons expressed SP-like immunoreactivity (LI) 14 days, but not 7 days after chamber application and constituted about 30% of all growing axons in the first segment. The SP-LI fibres also appeared to grow from the distal stump since they were found in larger numbers in the distal segments than in central ones. Those fibres accompanying blood vessels are probably sympathetic. Our findings demonstrate that axons are able to bridge a 10 mm gap within 14 days under appropriate substrate conditions, which are provided by the resorbable fibrin sponge.

Recovery of non-specific cholinesterase activity in sensory corpuscles of mouse toe skin after irreversible inhibition of this enzyme and cold injury.

Mouse digital corpuscles, located in the dermal papillae of toe pad skin, consist of the sensory axon terminals enveloped by the cytoplasmic processes of Schwann-derived cells forming the so-called inner core. The inner core cells are capable to synthetize nCHE molecules which are released into the interlamellar spaces filled by the basal lamina, collagenous microfibrils, and amorphous matrix. In the present study, the histochemical detection of the nCHE activity was investigated in the sensory corpuscles after sciatic and saphenous nerve transections and subsequent application of irreversible nCHE inhibitor (iso-OMPA) or cryo-treatment of toe pad skin. The recovery of the nCHE reaction product in both intact and denervated corpuscles revealed the resynthesis of the nCHE molecules by the inner core cells without assistance of sensory terminals, as well. The cellular constituents of corpuscles were degraded while extracellular matrix appeared to be undamaged after freezing injury. The molecules of nCHE attached to the extracellular matrix components disappeared in coincidence with the disintegration of Schwann-derived cells. After about 5 d of survival, the Schwann cells exhibiting the nCHE reactivity migrated through the basal lamina tubes as guidance of regrowing axons or alone. After 7 d from the treatment, immature Schwann cells marked by the nCHE reaction product occupied the scaffolds of old damaged sensory corpuscles. During further days of surviving, the Schwann cells entering the extracellular matrix of degraded corpuscles were differentiated to the inner core cells. The re-differentiation of the Schwann cells into the inner core cells was observed not only in the presence but also in the absence of sensory terminals. These findings suggest certain trophic independence of inner core cells upon sensory terminals in the sensory corpuscles of adult animals.