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Cellular Migration Associated With Macular Hole
A New Method for Comprehensive Bird’s-Eye Analysis of the Internal Limiting Membrane
Toshio Hisatomi, MD, PhD;
Hiroshi Enaida, MD, PhD;
Taiji Sakamoto, MD, PhD;
Takaaki Kanemaru, MD;
Tadahisa Kagimoto, MD;
Ichiro Yamanaka, MD, PhD;
Akifumi Ueno, MD;
Takao Nakamura, MD, PhD;
Yasuaki Hata, MD, PhD;
Tatsuro Ishibashi, MD, PhD
Arch Ophthalmol. 2006;124:1005-1011.
ABSTRACT
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Objective To elucidate the pathogenesis of macular hole formation, focusing in particular on the possible role of cellular migration on the cortical vitreous and internal limiting membrane (ILM) around the macular hole.
Methods To gain a comprehensive overview of the ILM excised in macular hole surgery (n = 36), the ILMs were carefully unfolded and spread out onto glass slides as continuous flat sheets that each contained a macular hole. The specimens were observed by light microscopy and transmission electron microscopy (n = 9), and the cellular distribution was analyzed by scanning electron microscopy in a quantitative manner (n = 27). Immunohistochemistry for glial fibrillary acidic protein and cytokeratin 18 was carried out for cellular characterization. Cellular proliferation was assessed by immunohistochemistry for proliferating cell nuclear antigen and Ki-67.
Results Cellular migration was not apparent around the macular hole in the early stage of development of the macular hole (stage 2, 0 µm). As the macular hole passed through the later stages of development, cellular migration developed around the macular hole (stage 3, 84 µm) and the area of cellular migration gradually enlarged (stage 4, 420 µm). The immunophenotypic analysis showed that these cells were mainly glial fibrillary acidic protein–positive glial cells and cytokeratin 18–positive retinal pigment epithelial cells. The proliferating cell nuclear antigen and Ki-67 immunohistochemistry showed that some of these cells were proliferating on the ILM.
Conclusions Cellular migration on the ILM is not necessary for the initial formation of a macular break. Cellular migration developed after the macular break occurred, and the migration and proliferation increased gradually from the macular hole.
Clinical Relevance This study provides a new method for understanding the ultrastructural analysis of the pathogenesis of the macular hole.
INTRODUCTION
The pathogenesis of the idiopathic macular hole is still not fully understood; however, there is agreement on the important role of vitreous attachment and vitreous traction to the underlying internal limiting membrane (ILM) and the retina in the developmental process of the macular hole. Avila et al1 and Kakehashi et al2 proposed that anteroposterior traction in the vitreous can cause a macular break. It was suggested that contraction of the prefoveal vitreous cortex might cause tangential traction leading to a macular tear.3-6 It was also suggested that the premacular vitreous cortex is the posterior wall of the vitreous pocket and that anterior traction by premacular vitreous cortex would lead to intraretinal cyst formation at the fovea following macular hole formation.7-9 In recent years, ultrasonography,10-11 confocal laser tomography,12-14 and optical coherence tomography15-21 have provided high-resolution cross-sectional images of the retina and vitreous in vivo. Gass3, 5 proposed a classification for the development of a macular hole according to 4 stages. Stage 1 is characterized by focal retinal detachment, stage 2 by early hole formation, stage 3 by a fully developed macular hole without posterior vitreous detachment (PVD), and stage 4 by a macular hole with PVD.
Cellular migration is hypothesized to be one of the major causes of contraction of extracellular matrix such as vitreous cortex.22-24 Some biomicroscopical studies and histological examinations of surgical and postmortem specimens have identified premacular tissue that may cause tangential traction to the retina.22, 25-27 In addition, histological examinations of excised ILMs demonstrated that migrating cells of various origins were located on the ILM and that these cells were associated with collagen fibers of various diameters.26-28 Other histological studies22, 25, 29 examining postmortem eyes with macular holes noted a high incidence of epiretinal formation in the macular area of the eyes. However, their detailed pathogenesis, especially the role and involvement of cellular migration on the ILM, still remains unclear.
We propose a new method for a topographic bird’s-eye analysis of the whole excised ILM. In this study, we describe detailed structures of the ILM around the idiopathic macular hole, the complex association of migrating and proliferating cells, and the extracellular matrix conferred by the developing stages of the macular hole. We examine the characterization and the proliferation of the distributing cells around the macular hole on the ILM.
METHODS
ILM PEELING PROCEDURE
Thirty-nine eyes of 38 patients who were diagnosed as having various stages of the idiopathic macular hole were prospectively studied clinically from January 2002 to July 2004. Biomicroscopical analysis of both the macular and vitreomacular relationships was carried out to identify the macular hole, and each was then graded according to the classification developed by Gass.3, 5, 30 A high-resolution optical coherence tomographic examination was used to confirm the state of PVD in each case. The stages of development of the macular holes were confirmed as stage 2 in 8 eyes, stage 3 in 13 eyes, and stage 4 in 15 eyes (total, 36 eyes). All of the data accumulation was carried out with approval from the ethics committee of Kyushu University, Fukuoka, Japan, and was performed in accordance with ethical standards in the 1989 Declaration of Helsinki. After informed consent was obtained from each patient, the patients underwent a standard 3-port pars plana vitrectomy. Balanced salt solution (BSS Plus; Alcon Laboratories, Fort Worth, Tex) was used as an irrigation solution. Triamcinolone acetonide (Kenakolt-A; Bristol Pharmaceuticals KK, Tokyo, Japan), a water-insoluble white corticosteroid, was used for visualizing the vitreous hyaloid as previously described31-34 (in a 1.0-mL triamcinolone acetonide suspension). If necessary, posterior hyaloid detachment was induced by suction or forceps around the optic nerve head. The vitreous was removed and PVD was extended to the periphery. The ILM was then peeled off with ILM forceps intended to be 3 disc diameters surrounding the macular hole, and fluid-gas exchange was performed through an extrusion cannula over the optic nerve head and macular hole. Twenty-percent sulfahexafluoride gas was then injected after closure of the scleral incisions. Postoperatively, patients were asked to keep a face-down position for at least 5 days.
TRANSMISSION ELECTRON MICROSCOPY OF THE EXCISED ILM
To carry out transmission electron microscopy, the 12 excised specimens (stage 2 in 4 eyes, stage 3 in 4 eyes, and stage 4 in 4 eyes) were immediately placed in 4% glutaraldehyde for fixation. Of the 12 specimens, 9 of them (stage 2 in 3 eyes, stage 3 in 3 eyes, and stage 4 in 3 eyes) were then postfixed in 2% veronal acetate buffer osmium tetroxide, dehydrated in ethanol and water, and embedded in Epon.35 Ultrathin sections were cut from blocks and mounted on copper grids. The specimens were observed with a JEM 100CX electron microscope (JEOL, Tokyo). Three specimens were further examined by flat-preparation transmission electron microscopy.
FLAT-PREPARATION TRANSMISSION ELECTRON MICROSCOPY
Three fixed specimens (stage 2 in 1 eye, stage 3 in 1 eye, and stage 4 in 1 eye) were dehydrated in ethanol and water, extracted as flat sheets with fine needles under a biomicroscope equipped with dark-field illumination (Nikon, Tokyo), and placed onto a glass slide. Then, the expanded ILMs were embedded in Epon. Ultrathin sections were cut from blocks and mounted on copper grids. The specimens were observed with a JEM 100CX electron microscope.
FLAT PREPARATION FOR COMPREHENSIVE BIRD’S-EYE ANALYSIS OF THE ILM
For scanning electron microscopy, 27 specimens were processed. Fifteen of the excised specimens were fixed in 4% glutaraldehyde. Twelve of the specimens were fixed in 4% paraformaldehyde for light microscopy and immunohistochemistry and then were analyzed by scanning electron microscopy. The fixed ILM was extracted as a flat sheet with fine needles under a biomicroscope equipped with dark-field illumination (Nikon) and placed onto a glass slide. When at least one fourth of the complete macular hole was clearly recognized on the expanded ILM (n = 23; 4 specimens were excluded from the total of 27 specimens; Table), immunochemistry, scanning electron microscopy, and cellular distribution studies were carried out. Two specimens were stained by hematoxylin-eosin and observed by light microscopy.
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Table. Summary of the 27 Excised Internal Limiting Membranes Analyzed by Scanning Electron Microscopy From Various Stages of Development of the Macular Hole*
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IMMUNOHISTOCHEMISTRY OF THE EXPANDED ILM
The ILMs were fixed in 4% paraformaldehyde in phosphate-buffered saline, extracted as whole sheets, and placed onto a glass slide (n = 8). The specimens were air dried. The first antibodies against glial fibrillary acidic protein (Dako, Tokyo) (n = 4), cytokeratin 18 (Chemicon, Temecula, Calif) (n = 4), proliferating cell nuclear antigen (PCNA) (Chemicon) (n = 2), and Ki-67 (Dako) (n = 2) were used for 2 hours at room temperature. The second antibodies labeled with Cy5 (Zymed Laboratories, San Francisco, Calif) and rhodamine (Cappel, Aurora, Ohio) were used for 1 hour at room temperature. The specimens were also stained with 4",6-diamino-2-phenylindole dihydrochloride for nuclear staining and observed with a fluorescence microscope (Table). The immunohistochemical control experiments included a negative control and an isotype control using the specific IgG subtype. All of the specimens for immunohistochemistry were dehydrated in ethanol and water and then analyzed by scanning electron microscopy.
SCANNING ELECTRON MICROSCOPY
The expanded ILMs were dehydrated in ethanol and water on a glass slide. The specimens were saturated in t-butyl alcohol, and critical-point drying (Eiko, Tokyo) was performed. The glass slide was cut into a 10-mm square. The specimens were then placed on stubs by means of self-adhering carbon tabs and sputtered with gold of 20-nm thickness by an argon plasma coater (Eiko).36-37 The specimens were observed with a JSM 840 electron microscope (JEOL).
CELLULAR DISTRIBUTION ON THE ILM
Cellular distribution was observed in 23 specimens (stage 2 in 5 eyes, stage 3 in 8 eyes, and stage 4 in 10 eyes) (Table) by scanning electron microscopy, and the results were analyzed according to the macular hole staging proposed by Gass.3, 5, 30 The distance from the top of the cellular distribution to the edge of the macular hole on the ILM was measured and analyzed using analysis software (MacScope; Mitani, Fukui, Japan). The results were expressed as means ± SDs. The t test was used to calculate the probability by comparing data between the groups, and P<.05 was considered to be statistically significant.
RESULTS
VERTICAL ANALYSIS OF PEELED ILM
Light microscopical examination of semithin sections showed characteristic sinusoidal folds of complexly folded ILM (Figure 1A). Transmission electron microscopy showed collagen membranous tissue with a smooth inner (vitreous) surface and an irregular outer (retinal) surface (Figure 1B). In the early stage of the macular hole (stage 2), cellular migration was rarely seen (Figure 1B). Some cells, namely, glial cells, retinal pigment epithelial cells, and origin-unknown fibroblast-like cells, were seen on the inner surface of the ILM in the middle stages (stage 3) (Figure 1C) of the macular hole and were seen often in the later stages (stage 4) (Figure 1D). Some cellular membranes and organelles derived from underlying Muller cells were occasionally seen on the outer surface of the ILM; however, there were no changes according to the stage of development of the macular holes (Figure 1B-D). We could not identify the location of the macular hole in complexly folded ILM by ultrathin cross sections.
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Figure 1. Vertical analysis of the excised internal limiting membrane (ILM). A, Light micrograph of a semithin section of the ILM stained by Azur II, showing characteristic sinusoidal folding (original magnification x100). B, Transmission electron microscopy showed collagen membranous tissue with a smooth inner (vitreous) surface and an irregular outer (retinal) surface. In the early stage of the macular hole (stage 2), cells were rarely seen. The extracellular matrix, namely, posterior vitreous hyaloid, was seen on the excised ILM intermingled with the distributed cells (arrowhead) (original magnification x2000). C, Some migrating cells (arrow) were seen on the inner surface of the ILM in stage 3 of development of the macular hole. Again, the extracellular matrix, namely, posterior vitreous hyaloid, was seen on the excised ILM intermingled with the distributed cells (arrowhead) (original magnification x2000). D, In the later stage (stage 4), significant cellular migration (arrows) was observed on the ILM. The extracellular matrix, namely, posterior vitreous hyaloid, was seen on the excised ILM intermingled with the distributed cells (arrowhead) (original magnification x2000).
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HORIZONTAL ANALYSIS OF EXPANDED ILM
Light microscopical examination of the excised whole ILM (Figure 2A) spread out onto a glass slide showed the intact ILM sheet containing a macular hole (Figure 2B). Dark-field illumination micrography showed that the ILM had the characteristic multilinear pattern associated with the underlying nerve fibers of the ganglion cells (Figure 2C). The hematoxylin-eosin–stained section showed migrating cells around the macular hole (stage 4) (Figure 2D). A few pigmented cells were seen among the distributing cells around the macular hole on the ILM (Figure 2E).
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Figure 2. Topographic bird’s-eye analysis of the internal limiting membrane (ILM) by light microscopy and fluorescence microscopy. The complexly folded excised ILM (A) extended onto a glass slide showed the intact ILM sheet containing an ILM defect corresponding to the area of the macular hole (asterisk) (B) (original magnification x4). C, A dark-field illumination image showed that the ILM has the characteristic multilinear pattern associated with the underlying nerve fibers of the ganglion cells (original magnification x10). D, The hematoxylin-eosin–stained section showed migrating cells around the macular hole (asterisk) (original magnification x200). E, Some of the cells on the ILM were pigmented cells (arrows) (original magnification x400).
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IMMUNOHISTOCHEMICAL ANALYSIS
Immunohistochemical analysis revealed that most of the dispersed cells on the ILM were glial fibrillary acidic protein–positive glial cells (Figure 3A). There were also cytokeratin 18–positive retinal pigment epithelial cells among the glial cells (Figure 3A). These cells formed a continuous cellular sheet around the macular hole on the ILM. To i nvestigate whether these cells were migrating and/or proliferating on the ILM, we examined their proliferation by 2 different proliferating cell markers, PCNA and Ki-67. Proliferating cell nuclear antigen is a 36-kd proliferation-associated antigen, and Ki-67 is a large nuclear antigen preferentially expressed during all of the active phases of the cell cycle but absent in resting cells. Nuclear staining by 4",6-diamino-2-phenylindole dihydrochloride showed chromosomes of dividing nuclei (Figure 3B). Both PCNA and Ki-67 showed positive staining in the nucleus of the proliferating cells (Figure 3C and D). The PCNA-positive cells and Ki-67–positive cells accounted for 7% and 9%, respectively, of the total cells on the ILM. The proliferating cells dispersed around the distributed cells around the macular hole, and an obvious proliferating front was not observed in the specimens.
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Figure 3. Immunohistochemical analysis of the distributed cells on the internal limiting membrane. A, Double immunohistochemistry of glial fibrillary acidic protein (green) and cytokeratin 18 (red) showed a mosaic-like migration pattern of glial fibrillary acidic protein–positive glial cells and cytokeratin 18–positive retinal pigment epithelial cells. Some of the cytokeratin 18–positive cells were pigmented (arrow) (original magnification x200). B, Nuclear staining by 4",6-diamino-2-phenylindole dihydrochloride showed chromosomes of dividing nuclei (arrows) (original magnification x1000). Immunohistochemistry of proliferating cell nuclear antigen (C) and Ki-67 (D) showed proliferating cells (arrowheads) among the distributed cells on the internal limiting membrane (original magnification x400).
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VERTICAL ANALYSIS OF EXPANDED ILM
Light microscopical examination of semithin sections of the expanded ILM showed a linear shape of the ILM (Figure 4A). On the expanded ILM, few Azur II–stained cells were shown around the ILM defect corresponding to the area of the macular hole at stage 4, providing better spatial understanding of the ILM. Transmission electron microscopy demonstrated the expanded linear ILM and migrating cells (Figure 4B) as well as dense collagen fibers, namely, residual posterior hyaloid between the ILM and migrating cells (Figure 4C).
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Figure 4. Vertical observation of the expanded internal limiting membrane (ILM). A, Light microscopical examination of a semithin section of the expanded ILM showed the linear shape of the ILM. On the expanded ILM, few Azur II–stained cells were seen around the ILM defect corresponding to the area of the stage 4 macular hole (asterisk) (original magnification x600). Transmission electron microscopy showed the expanded linear ILM and migrating cells (original magnification x2000) (B) as well as dense collagen fibers, namely, residual posterior vitreous hyaloid between the ILM and migrating cells (original magnification x6600) (C).
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SCANNING ELECTRON MICROSCOPY
Scanning electron microscopy revealed a smooth inner surface (Figure 5A) and rough outer surface (Figure 5B) of the ILM. This dense collagen layer is a basement membrane of Muller cells, namely, the ILM, and demonstrates the characteristic smooth surface. Neither fibrous collagen nor fibrillar vitreous collagen are smooth surfaced by scanning electron microscopy. In the early stages of development of the macular hole, migrating cells were not apparent on the inner surface of the ILM around the macular hole (Figure 5A). Notably, in the later stages, migrating cells were clearly visible around the ILM defect corresponding to the area of the macular hole (Figure 5C), indicating that these cells were migrating away from the macular hole. Cellular migration occurred on the ILM, showing flat and sticking morphological features and spreading filopodia on the ILM (Figure 5D). A topographic image of the expanded ILM showed no cellular migration around the ILM defect corresponding to the area of the macular hole at stage 2 (Figure 5E).
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Figure 5. Topographic analysis of the internal limiting membrane (ILM) by scanning electron microscopy. Scanning electron microscopy revealed a smooth inner surface of the excised ILM, where migrating cells from the macular hole were rarely seen in the early stage (stage 2) of development of the macular hole (A), and revealed a rough outer surface of the excised ILM (B) (original magnification x3000). Migrating cells from the macular hole were more prominent in the later stage (stage 4) of development of the macular hole (original magnification x1800) (C), showing flat and sticking morphological features and spreading filopodia on the ILM (original magnification x8000) (D). E, A topographic bird’s-eye view of the expanded ILM showed no cellular migration around the ILM defect corresponding to the area of the stage 2 macular hole (asterisk) (original magnification x75).
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CELLULAR MIGRATION FROM THE MACULAR HOLE
The distance of cellular migration from the ILM defect corresponding to the area of the macular hole gradually increased through each stage of development of the macular hole (Figure 6). The cellular migration occurred from the edge of the macular hole and developed to the peripheral area of the ILM (Figure 6A-C). In most cases, cellular migration was observed as a continuous sheet of cells around the macular hole (Figure 6B and C).
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Figure 6. Quantitative analysis of cellular migration from the macular hole. The representative developmental stages of cellular migration on the internal limiting membrane from the internal limiting membrane defect corresponding to the area of the macular hole (asterisks) are shown for stage 2 (A), stage 3 (B), and stage 4 (C) (original magnification x140). D, The distance of cellular migration from the edge of the macular hole was measured and analyzed using analysis software (MacScope; Mitani, Fukui, Japan). The t test was used to calculate the probability by comparing data between the groups, and P<.05 was considered to be statistically significant (asterisks). The area of cellular migration gradually enlarged as the macular hole passed through the later stages of development. Error bars indicate SDs.
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COMMENT
This study demonstrates that cellular migration around the macular hole develops after the macular break occurs and that cellular migration occurs from the macular hole and enlarges on the ILM. To our knowledge, this is the first article clearly showing that cellular migration on the ILM is not necessary for the initial formation of a macular break.
COMPREHENSIVE TOPOGRAPHIC ANALYSIS OF EXCISED ILM
Some previous histological studies26-28 demonstrated cellular migration on the ILM around the macular hole; however, this was based on findings from the ultrathin partial cross sections of the ILM, leaving the origin and distribution of the cells largely unknown, as shown in Figure 1. We propose a topographic analysis of the whole excised ILM that enables understanding of cellular migration, especially its origin, frequency, distribution, and relationship with the macular hole (Figure 6). Whereas a cross section gives a snapshot of a limited area of excised complexly folded ILM at a particular time point (Figure 1), horizontal observation enables a comprehensive analysis of spatial distribution that offers a temporal perspective of cellular migration around a macular hole in its process of development (Figure 6).
DISTRIBUTED CELLS AROUND THE MACULAR HOLE
The ultrastructural studies23, 27-28,38 of migrating cells and epiretinal membranes have found them to be glial cells, retinal pigment epithelium, myofibroblasts, and so on. Our light microscopical studies demonstrate that some of the migrating cells were pigmented cells (Figure 2E), and immunohistochemical studies also demonstrate a mosaic-like migration pattern of glial fibrillary acidic protein–positive glial cells and cytokeratin 18–positive retinal pigment epithelial cells (Figure 3A). These cells were intermingled to form an epiretinal membrane as a continuous cellular sheet on the ILM (Figure 2E, Figure 3A, Figure 4B, and Figure 5C). To further estimate the cellular proliferation on the ILM, we examined their proliferation by 2 different proliferating cell markers, PCNA and Ki-67. Although the proliferating cells dispersed around the distributed cells around the macular hole, an obvious proliferating front was not observed in the specimens.
ROLE OF CELLULAR MIGRATION IN THE PATHOGENESIS OF THE MACULAR HOLE
Figure 6A shows a complete lack of cellular migration in the early stage (stage 2) of development of the macular hole. In contrast, Figure 6B shows cellular development around the edge of the macular hole, and Figure 6C shows a large amount of cellular migration from the macular hole to the peripheral area. Notably, in the later stage of development of the macular hole, some specimens showed no cellular migration around the macular hole (Table). Our results confirm that the initial break of the macular hole is not dependent on cellular migration around the macular hole (Figure 6D). In contrast, cellular migration developed after the macular break and expanded from the edge of the macular hole to the periphery (Figure 4A and Figure 6A-C), finally forming an epiretinal membrane on the ILM. This cellular migration and its contraction of the extracellular matrix on the ILM (Figure 1B-D and Figure 4) might lead to further progression of the macular hole (stage 3) and might keep the macular hole open even after PVD (stage 4).
The role of cellular migration in the pathogenesis of the macular hole remains quite unclear. We provide a comprehensive bird’s-eye analysis of the ultrastructure of the ILM and demonstrate cellular migration and proliferation in a quantitative manner, proposing the association of cellular migration to the pathogenesis of a macular hole.
AUTHOR INFORMATION
Correspondence: Toshio Hisatomi, MD, PhD, Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (hisatomi{at}med.kyushu-u.ac.jp).
Submitted for Publication: September 8, 2004; final revision received April 14, 2005; accepted April 19, 2005.
Financial Disclosure: None reported.
Funding/Support: This work was supported in part by grants-in-aid for scientific research 16791052 from the Japanese Ministry of Education, Science, Sports, and Culture, Tokyo.
Acknowledgment: We thank Eve Sockett for editing the manuscript.
Author Affiliations: Department of Ophthalmology (Drs Hisatomi, Enaida, Kagimoto, Yamanaka, Ueno, Nakamura, Hata, and Ishibashi) and Morphology Core (Dr Kanemaru), Graduate School of Medical Sciences, Kyushu University, Fukuoka, and Department of Ophthalmology, Kagoshima University School of Medicine, Kagoshima (Dr Sakamoto), Japan.
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