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PubMed2006

BDNF production by olfactory ensheathing cells contributes to axonal regeneration of cultured adult CNS neurons.

Olfactory ensheathing cells (OECs) are the main glial cell type that populates mammalian olfactory nerves. These cells have a great capacity to promote the regeneration of axons when transplanted into the injured adult mammalian CNS. However, little is still known about the molecular mechanisms they employ in mediating such a task. Brain-derived neurotrophic factor (BDNF) was identified as a candidate molecule in a genomic study that compared three functionally different OEC populations: Early passage OECs (OEC Ep), Late passage OECs (OEC Lp) and the OEC cell line TEG3 [Pastrana, E., Moreno-Flores, M.T., Gurzov, E.N., Avila, J., Wandosell, F., Diaz-Nido, J., 2006. Genes associated with adult axon regeneration promoted by olfactory ensheathing cells: a new role for matrix metalloproteinase 2. J. Neurosci. 26, 5347-5359]. We have here set out to determine the role played by BDNF in the stimulation of axon outgrowth by OECs. We compared the extracellular BDNF levels in the three OEC populations and show that it is produced in significant amounts by the OECs that can stimulate axon regeneration in adult retinal neurons (OEC Ep and TEG3) but it is absent from the extracellular medium of OEC Lp cells which lack this capacity. Blocking BDNF signalling impaired axonal regeneration of adult retinal neurons co-cultured with TEG3 cells and adding BDNF increased the proportion of adult neurons that regenerate their axons on OEC Lp monolayers. Combining BDNF with other extracellular proteins such as Matrix Metalloproteinase 2 (MMP2) further augmented this effect. This study shows that BDNF production by OECs plays a direct role in the promotion of axon regeneration of adult CNS neurons.

Animals↗
PubMed2004

Intraocular implantation of DNA-transfected retinal pigment epithelium cells: a new approach for analyzing molecular functions in the newt retinal regeneration.

Adult newts can regenerate their entire retinas, even after surgical removal of the neural retina (retinectomy), through transdifferentiation of the retinal pigment epithelium (RPE) cells. To develop a new experimental system for analyzing molecular functions during retinal regeneration of adult newts, we attempted to deliver a foreign gene into RPE cells of retina-less eye-cups in vitro. Here we used pCS2mt-GFP as a reporter construct, and selected Polyfect as a transfection reagent. DNA-transfection appeared to be restricted to the RPE cells of retina-less eye-cups and its efficiency was 0.1-0.2%. We tried to implant RPE-choroid tissue containing DNA-transfected RPE cells into the eye of a host animal. The tissue was placed into the posterior eye-chamber immediately after retinectomy so that the implanted RPE tissue was facing the cornea (i.e., normal orientation). The implant and host RPE regenerated one continuous hybrid neural retina. Ocular sections after 60 days of implantation showed that a small number of cells in the regenerating retina were intensely stained with an anti-GFP antibody. Some of those cells were believed to be retinal cells such as ganglion cells, amacrine cells and photoreceptors. The GFP-positive cells in the hybrid regenerating retina could represent clones derived from a single RPE cell. These results indicate that this experimental system could become useful in the study of adult newt retinal regeneration.

Animals↗
PubMed2006

Protracted myelin clearance hinders central primary afferent regeneration following dorsal rhizotomy and delayed neurotrophin-3 treatment.

Regeneration within or into the CNS is thwarted by glial inhibition at the site of a spinal cord injury and at the dorsal root entry zone (DREZ), respectively. At the DREZ, injured axons and their distal targets are separated by degenerating myelin and an astrocytic glia limitans. The different glial barriers to regeneration following dorsal rhizotomy are temporally and spatially distinct. The more peripheral astrocytic barrier develops first, and is surmountable by neurotrophin-3 (NT-3) treatment; the more central myelin-derived barrier, which prevents dorsal horn re-innervation by NT-3-treated axons, becomes significant only after the onset of myelin degeneration. Here we test the hypothesis that in the presence of NT-3, axonal regeneration is hindered by myelin degeneration products. To do so, we used the Long Evans Shaker (LES) rat, in which oligodendrocytes do not make CNS myelin, but do produce myelin-derived inhibitory proteins. We show that delaying NT-3 treatment for 1 week in normal (LE) rats, while allowing axonal penetration of the glia limitans and growth within degenerating myelin, results in misdirected regeneration with axons curling around presumptive degenerating myelin ovoids within the CNS compartment of the dorsal root. In contrast, delaying NT-3 treatment in LES rats resulted in straighter, centrally-directed regenerating axons. These results indicate that regeneration may be best optimized through a combination of neurotrophin treatment plus complete clearance of myelin debris.

Afferent Pathways↗
PubMed2004

Vesicular acetylcholine transporter can be a morphological marker for the reinnervation to muscle of regenerating motor axons.

This study was designed to evaluate whether the vesicular acetylcholine transporter (VAChT), which packages acetylcholine into synaptic vesicles, can be used as a marker for regenerating motor axon terminal. We examined motor axon regeneration in the tongue after hypoglossal nerve axotomy, using an anterograde tracer biotin-dextran (BD), retrograde tracer Fluoro-Gold (FG), electron microscopic (EM) observation, and VAChT immunocytochemistry. BD study demonstrated that outgrowth of thin regenerating axons into the frontal area of the tongue was firstly observed at 14 post-operative days, and presynaptic formation of neuromuscular junction (NMJ) was observed from 21 post-operative days. Under electron microscopic observation, reconstruction of new NMJs was observed within the interval between 21 and 28 days. VAChT-immunoreactive nerve terminals disappeared by 3 days after axotomy, slightly appeared at 14 post-operative days, and thereafter gradually increased in number from 21 to 28 post-operative days. The re-expression of VAChT positive presynaptic terminal was almost the same as those obtained in BD, FG and EM studies. Regenerating axons tip in the crush model of the hypoglossal nerve exhibited prominent VAChT immunoreactivity in growing tip of regenerating axons. These indicate that VAChT is an excellent morphological indicator for regenerating nerve terminals of motor neurons.

Animals↗
PubMed2004

Developmental regulation of homeobox gene expression in dorsal root ganglion neurons is not recapitulated during regeneration of the crushed sciatic nerve.

The adult peripheral nervous system is able to regenerate after injury. Regeneration is associated with the expression of new genes and proteins. Proteins abundant in developing axons increase in expression after injury, whereas proteins involved in neurotransmission are downregulated. It has been hypothesized that molecular mechanisms underlying regeneration-associated alterations in gene expression may be a recapitulation of developmental processes. These gene expression changes are likely to be regulated by changes in the gene expression of transcription factors. As homeobox genes play important roles in embryonic development of the nervous system, it makes them candidates for a regulatory role in the process of regeneration. Here we show that the relative mRNA expression levels of Isl1 decreased shortly after crush, but those of DRG11, Lmx1b, and Pax3 did not change after crush. These data indicate that the developmental expression patterns of the homeobox genes studied here are not recapitulated during regeneration of the dorsal root ganglia neurons. We conclude that developmental gene expression programs controlled by these homeobox genes are not directly involved in sciatic nerve regeneration.

Animals↗
PubMed2004

[11C]choline uptake in regenerating liver after partial hepatectomy or CCl4-administration.

To characterize [methyl-(11)C]choline ([(11)C]choline) as an oncologic PET radiopharmaceutical, [(11)C]choline uptake in regenerating livers after partial hepatectomy as a model of typical proliferating tissue and after CCl(4) insult as that of proliferating tissue with inflammation, was studied in rats. [(11)C]Choline, [(18)F]2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) and [2-(14)C]thymidine ([(14)C]TdR) uptake was studied in regenerating rat liver after 70% partial hepatectomy or CCl(4)-administration. [(11)C]Choline uptake in regenerating liver after partial hepatectomy was significantly increased with [(14)C]TdR uptake as a marker of DNA synthesis at 18 hours after surgery. On the other hand, the uptake was not accelerated by CCl(4)-administration, though it significantly increased [(14)C]TdR uptake. There were no differences of [(11)C]choline uptake acceleration following partial hepatectomy among the three parts of the regenerating liver. [(18)F]FDG uptake was accelerated in the regenerating liver on either partial hepatectomy or CCl(4)-administration. The magnitude of the increase in [(18)F]FDG uptake in the regenerating liver induced by partial hepatectomy was greater than that for [(11)C]choline. [(11)C]Choline uptake in the liver was accelerated by partial hepatectomy, but not by CCl(4)-administration. This might be expected given that the differentiation between proliferating tissues such as tumor and inflammatory tissue was possible by [(11)C]choline-PET.

Animals↗
PubMed2005

Augmented hepatic injury followed by impaired regeneration in metallothionein-I/II knockout mice after treatment with thioacetamide.

A previous study (Oliver, J.R., Mara, T.W., Cherian, M.G. 2005. Impaired hepatic regeneration in metallothionein-I/II knockout mice after partial hepatectomy. Exp. Biol. Med. 230, 61-67) has shown an impairment of liver regeneration following partial hepatectomy (PH) in metallothionein (MT)-I and MT-II gene knockout (MT-null) mice, thus suggesting a requirement for MT in cellular growth. The present study was undertaken to investigate whether MT may play a similar role in hepatic injury and regeneration after acute treatment with thioacetamide (TAA). Hepatotoxicity of TAA is caused by the generation of oxidative stress. TAA was injected ip to both wild-type (WT) and MT-null mice. Mice were killed at 6, 12, 24, 48, 60, and 72 h after injection of TAA (125 mg/kg) or 48 h after injection of saline (vehicle control), and different parameters of hepatic injury were measured. The levels of hepatic lipid peroxidation were increased at 12 h in both types of mice; however, lipid peroxidation was significantly less in WT mice than MT-null mice at 48 h after injection of TAA. Analysis of hepatic glutathione (GSH) levels after TAA injection showed depletion of GSH at 12 h in WT mice and at 6 h in MT-null mice; however, significantly more GSH was depleted early (6-24 h) in MT-null mice than WT mice. An increase in hepatic iron (Fe) levels was observed in both types of mice after injection of TAA, but Fe levels were significantly higher in MT-null mice than WT mice at 6-60 h. The levels of hepatic copper (Cu) and zinc (Zn) were significantly higher in WT mice than MT-null mice at 6-60 h for Cu, and at 24 h and 60 h for Zn, respectively. Histopathological examination showed hemorrhagic necrosis in the liver of both types of mice at 12-72 h, with hepatic injury being more prominent in MT-null mice than WT mice. The hepatic MT levels were increased in WT mice after injection of TAA, and were highest at 24-72 h. Immunohistochemical staining for MT in WT mice indicated the presence of MT in both nucleus and cytoplasm of hepatocytes at 24-72 h after TAA injection. Cell proliferation, as assessed by immunohistochemical staining for proliferating cell nuclear antigen, was detected mainly in the livers of WT mice at 48-72 h after TAA treatment. Hepatic proliferation index in MT-null mice was very low as compared to WT mice during liver regeneration after injection of TAA. These results show that the liver cells of MT-null mice with no functional MT are unable to regenerate after TAA-induced hepatic injury, demonstrating an important role for MT in cellular regeneration.

Acute Disease↗
PubMed2003

Myotoxic phospholipases A2 and the regeneration of skeletal muscles.

The review explains why the myotoxic phospholipases A2 and cardiotoxins are such important tools in the study of the regeneration and maturation of mammalian skeletal muscle. The role of satellite cells as precursors of cell-based regeneration is discussed and recent controversies on the origin of myogenic cells involved in the regeneration of mature skeletal muscle are addressed. This is followed by discussions of sarcomere reconstruction, myosin and sarcoplasmic reticulum ATPase expression, the electrophysiological properties of regenerating muscle, and the reconstruction of the neuromuscular junction. The emphasis throughout is on the plastic changes of major structural and functional proteins that occur during regeneration, and on other influences that determine the final outcome of regenerative activity such as innervation, thyroid status, mechanical work and the functional integrity of the microcirculation. The review closes with a discussion of some of the factors--such as active regeneration--that influence the success of gene-based therapies applied to inherited muscle disease.

Adenosine Triphosphatases↗
PubMed2004

A novel role of the hedgehog pathway in lens regeneration.

Lens regeneration in the adult newt is a classic example of replacing a lost organ by the process of transdifferentiation. After lens removal, the pigmented epithelial cells of the dorsal iris proliferate and dedifferentiate to form a lens vesicle, which subsequently differentiates to form a new lens. In searching for factors that control this remarkable process, we investigated the expression and role of hedgehog pathway members. These molecules are known to affect retina and pigment epithelium morphogenesis and have been recently shown to be involved in repair processes. Here we show that Shh, Ihh, ptc-1, and ptc-2 are expressed during lens regeneration. The expression of Shh and Ihh is quite unique since these genes have never been detected in lens. Interestingly, both Shh and Ihh are only expressed in the regenerating and developing lens, but not in the intact lens. Interfering with the hedgehog pathway results in considerable inhibition of the process of lens regeneration, including decreased cell proliferation as well as interference with lens fiber differentiation in the regenerating lens vesicle. Down-regulation of ptc-1 was also observed when inhibiting the pathway. These results provide the first evidence of a novel role for the hedgehog pathway in specific regulation of the regenerating lens.

Animals↗
PubMed2006

Inhibition of BMP signaling during zebrafish fin regeneration disrupts fin growth and scleroblasts differentiation and function.

The zebrafish caudal fin provides a simple model to study molecular mechanisms of dermal bone regeneration. We previously showed that misexpression of Bone morphogenetic protein 2b (Bmp2b) induces ectopic bone formation within the regenerate. Here we show that in addition to bmp2b and bmp4 another family member, bmp6, is involved in fin regeneration. We further investigated the function of BMP signaling by ectopically expressing the BMP signaling inhibitor Chordin which caused: (1) inhibition of regenerate outgrowth due to a decrease of blastema cell proliferation and downregulation of msxb and msxC expression and (2) reduced bone matrix deposition resulting from a defect in the maturation and function of bone-secreting cells. We then identified targets of BMP signaling involved in regeneration of the bone of the fin rays. runx2a/b and their target col10a1 were downregulated following BMP signaling inhibition. Unexpectedly, the sox9a/b transcription factors responsible for chondrocyte differentiation were detected in the non-cartilaginous fin rays, sox9a and sox9b were not only differentially expressed but also differentially regulated since sox9a, but not sox9b, was downregulated in the absence of BMP signaling. Finally, this analysis revealed the surprising finding of the expression, in the fin regenerate, of several factors which are normally the signatures of chondrogenic elements during endochondral bone formation although fin rays form through dermal ossification, without a cartilage intermediate.

Animals↗
PubMed2002

Avian brainstem neurogenesis is stimulated during cochlear hair cell regeneration.

Unlike mammals, adult avians are able to regenerate cochlear sensory hair cells following injury. Brainstem auditory neurons in chicken nucleus magnocellularis (NM), which receive their sole excitatory afferent input from the cochlea, were examined for evidence of mitosis during ototoxin-induced loss and regeneration of cochlear hair cells. Using tritiated thymidine as a mitotic marker in tissue processed for autoradiography and counterstained with thionin, labeled NM neurons and glia were counted from chickens killed 16 days after gentamicin or saline injections. Newly generated NM neurons were observed during cochlear hair cell regeneration. More labeled neurons were observed in the experimental chickens, but a few were also seen in the control chickens. We predicted labeled NM neurons would be found solely in the rostral high frequency region, given the gentamicin-induced high frequency cochlear hair cell loss and regeneration. However, the labeled NM neurons were located throughout the tonotopic axis of the nucleus. The total number of labeled neurons was lower than predicted. Many labeled NM glia were observed in experimental and control chickens. Labeled cells were also observed throughout the chicken brainstem and cerebellum in both experimental and control chickens, indicating great potential for CNS plasticity. Results in NM indicate the avian auditory system is capable of regenerating brainstem auditory neurons in addition to the previously well-established capability of regenerating cochlear hair cells in response to ototoxic injury. Recovery of both central and peripheral auditory components will be necessary to restore hearing damaged by noise or ototoxic drugs.

Afferent Pathways↗
PubMed1987

Molecular differentiation of neurons from ependyma-derived cells in tissue cultures of regenerating teleost spinal cord.

Cells cultured from the caudalmost area of regenerating teleost spinal cord differ both morphologically and in terms of molecular architecture from those of more rostral (more fully differentiated) areas of the cord. The caudalmost regenerating cord consists of an ependymal tube. Cells from this region have flattened or partially flattened cell somas and short spike projections in vitro; they do not exhibit the rounded cell somas nor the long, thin, branching neurites typical of differentiated neurons. A series of cultures taken from different areas along the length of regenerating spinal cord were examined for molecular differentiation by staining with a monoclonal antibody against non-phosphorylated neurofilament protein (SMI 32). None of the cells from the caudalmost culture of the regenerating spinal cord stained with antibody SMI 32. In cultures of more rostral regenerated cord, the cells with neuronal morphology do stain positively with the anti-neurofilament antibody. This result suggests that the cells in the cultures of caudalmost cord represent relatively undifferentiated ependymal cells, or ependyma-derived cells, which later differentiate into neurons and glia in the regenerating spinal cord.

Animals↗
PubMed1997

Peripheral nerve regeneration through silicone chambers in streptozocin-induced diabetic rats.

The silicone chamber model was used to evaluate peripheral nerve regeneration (PNR) in streptozocin (STZ)-induced diabetic rats. Diabetic and control animals underwent sciatic nerve transection and silicone chamber implantation establishing gaps of various lengths between the transected nerve ends. In animals with 5 and 10 mm gaps, diabetes was induced in experimental rats 1 week before surgery, and the animals were sacrificed 3 weeks after surgery. In animals with 8 mm gaps, diabetes induction occurred 3 days after surgery, and they were sacrificed after 7 weeks. Diabetic rats with 10 mm gaps demonstrated an impaired ability to form bridging cables, the initial step of regeneration through chambers. Morphometric studies of bridging cables between transected nerve ends demonstrated a significant reduction in the mean endoneurial area in diabetic animals with 5 and 8 mm gaps compared to controls. The number of regenerated myelinated axons in the chamber was significantly decreased in diabetic rats with 8 and 10 mm gaps. The mean myelinated fiber area in the regenerated cables of the diabetic group was significantly decreased with 5 mm gaps and significantly increased with 8 mm gaps compared to controls. Size-frequency histograms of regenerated myelinated fiber areas suggest a delay in the maturation of small caliber axons. Schwann cell migration across 5 mm gaps was examined with S-100 immunohistochemistry. The total distance of Schwann cell migration into cables from both proximal and distal ends was significantly reduced in diabetic animals. Characterization of PNR across gaps through silicone chambers in diabetic rats showed impairment in multiple aspects of the regenerative process, including cable formation, Schwann cell migration, and axonal regeneration.

Animals↗
PubMed1998

Appearance of glutamate-like immunoreactivity during retinal regeneration in the adult newt.

The appearance of endogenous glutamate during retinal regeneration in the newt was examined by immunohistochemistry. Glutamate-like immunoreactivity (Glu-LI) first appeared in prospective ganglion cells along the vitreal margin of retinas that were about six cells thick, in prospective photoreceptors immediately before segregation of retinal plexiform layers and then in prospective bipolar cells immediately after the initial appearance of thin plexiform layers. In retinas nearing complete regeneration, Müller cells showed immunoreactivity. The appearance of glutamatergic phenotypes during retinal regeneration seemed to follow the order of cell differentiation [T. Saito, Y. Kaneko, F. Maruo, M. Niino, Y. Sakaki, Study of the regenerating newt retina by electrophysiology and immunohistochemistry (bipolar- and cone-specific antigen localization), J. Exp. Zool. 270 (1994) 491-500]. However, changes in the amount of endogenous glutamate during retinal regeneration were more complex. On the one hand, Glu-LI at the prospective ganglion cell layer temporarily increased during the initial period of segregation of the inner plexiform layer. On the other hand, immunoreactivity in the photoreceptor layer declined during segregation of the outer plexiform layer. The transient expression of immunoreactivity may represent a function of glutamate in events such as cell survival or neurite extension during retinal regeneration.

Animals↗
PubMed1998

Motoneurotrophins derived from limb buds protect the motoneurons in anterior spinal cord after nerve injury and promote nerve regeneration.

The effects of limb bud-derived motoneurotrophins (LBMNTs) as seen in the motoneurons in the anterior spinal cord and sciatic nerve regeneration of adult rats, were evaluated in the present study. A nerve regeneration chamber with a nerve gap of 9 mm was created by suturing the proximal and distal ends of a random sciatic nerve into a silicone tube after removal of a 5 mm piece of nerve in the distal end, The chamber of the experimental group was filled with 34.34 microg LBMNTs and PBS (0.01 mol/ml, pH 7.0),and the control group with PBS only. At 1 day, 4 days, 1 week, 2 weeks, 4 weeks and 6 weeks post surgery, the content of acetylcholine esterase (AchE) and acid phosphatase (ACP) of the anterior spinal cord (injured side) was quantified, and the corresponding motoneuron's ultrastructure and the existant ratio were also examined. Meanwhile, the regenerated nerve from within the silicone tube was examined at 2, 4 and 6 weeks post surgery for histological studies at both the light microscopic and ultrastructural levels. The experimental group showed a smaller decrease of AchE and an increase of ACP, a larger existant ratio of motoneurons, better ultrastructure and a more mature regenerated nerve based on a larger diameter of the regenerated nerve trunk, a greater number of axons and thicker myelin sheaths than the control group. So it was concluded that LBMNTs had a high activity of protecting motoneurons in the anterior spinal cord after nerve injury and promoting nerve regeneration, and it may be a new source of neurotrophic factors (NTFs).

Acetylcholinesterase↗
PubMed1997

Inter-relationships between angiogenesis and nerve regeneration: a histochemical study.

Whilst increases in capillary number and permeability occurring during nerve regeneration suggest an interaction between regenerating axons and blood vessels, clinical attempts to improve nerve regeneration by augmenting nerve graft vascularisation have produced conflicting results and the nature of their relationship remains obscure. A better understanding of the process might be exploited in the development of a synthetic alternative to the autologous nerve graft and bring an improvement in the clinical results of nerve repair. To clarify this relationship the growth of axons and blood vessels through mats of orientated fibronectin grafted in rat sciatic nerves was assessed morphologically. Fibronectin, which supports axonal regeneration, is initially acellular, ensuring all vascular and neural elements within the graft are newly formed. To follow the progression of the elements, grafts were harvested between 3 and 30 days and stained with antibodies against endothelial cells (RECA-1), Schwann cells (S-100) and axons (a polyclonal or monoclonal panaxonal marker). Dual fluorescence staining combined with double exposure photography allowed the simultaneous visualisation of these elements and the demonstration of their true relative positions. Graft vascularisation came initially from the adjacent muscle bed. A neovascularisation front preceded axonal regeneration, although vessel and axonal orientation appeared similar. Schwann cells and axons extended together, never exceeding the area of vascularisation and appeared most numerous in well vascularised areas containing longitudinally orientated vessels. These results suggest that provision of a well vascularised, longitudinally orientated conduit may enhance nerve regeneration.

Animals↗
PubMed2003

Increased light damage susceptibility at night does not correlate with RPE65 levels and rhodopsin regeneration in rats.

The susceptibility of rats to light-induced retinal degeneration is increased at night. In mice, an important determinant of light damage susceptibility is the efficacy of rhodopsin regeneration after bleaching. The rate of rhodopsin regeneration is at least partly controlled by RPE65, a protein expressed in the retinal pigment epithelium. We therefore tested a potential involvement of RPE65 and rhodopsin regeneration in the increased light damage susceptibility of rats at night. For this purpose, rats were exposed to visible light at noon or at midnight and extent of light damage was determined by retinal morphology and TUNEL staining. Rpe65 gene expression was analyzed by semiquantitative RT-PCR and levels of RPE65 protein were determined by Western blotting. Rhodopsin regeneration kinetics was determined by measuring rhodopsin content immediately after a strong bleach and after different times of recovery in darkness. Rats were more susceptible to light damage at night as described by Organisciak and collegues [Invest. Ophthalmol. Vis. Sci. 41 (2000) 3694]. Rpe65 gene expression followed a day-night rhythm with highest steady-state mRNA levels at the beginning and lowest levels at the end of the day period. However, RPE65 protein levels remained constant. Rhodopsin regeneration kinetics did not differ during day and night. We conclude that levels of RPE65 protein and rhodopsin regeneration kinetics do not correlate with the increased light damage susceptibility observed in rats at night. Additional genetic or physiologic modifiers may exist in rats that regulate the retinal responsiveness to acute light exposure.

Acute Disease↗
PubMed1987

Release of neuronotrophic factor from rabbit corneal epithelium during wound healing and nerve regeneration.

Epithelial neuronotropic factor (ENF) is secreted by cultured epithelial cells of rabbit cornea and conjunctiva, and is active in promoting survival and inducing neurite outgrowth of cultured trigeminal neurons. This study evaluated the relation of ENF to corneal nerve regeneration utilizing a model of heptanol-induced epithelial wounding. The organ culture technique was used to collect ENF from the intact corneal epithelium, and a neuronal bioassay was utilized to quantify ENF. The results revealed no change in ENF secretion either during initial wound closure or after 1 week, when the epithelium had regenerated. However, ENF secretion was elevated 2.4 times in 2 weeks after wounding. Morphometric analysis of corneal nerves stained by gold chloride impregnation showed that the first sign of regeneration of intraepithelial nerves was observed after 2 weeks, and the normal pattern of epithelial neural density was re-established after 3 weeks. However, the neural density was still subnormal (35-47% less than the control) in the wounded epithelium up to 4 weeks after wounding. Thus it appears that a surge in ENF secretion occurred after epithelial regeneration but before nerve regeneration. The results suggest that ENF may mediate corneal nerve regeneration.

Animals↗