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. 2023 Mar 31;30:101836. doi: 10.1016/j.ajoc.2023.101836

3-D OCT imaging of hyalocytes in partial posterior vitreous detachment and vaso-occlusive retinal disease

Sofia Ahsanuddin a,b, Hernan A Rios a,b, Jeffrey A Glassberg c,d, Toco YP Chui a,b, J Sebag e,f,g, Richard B Rosen a,b,∗
PMCID: PMC10139967  PMID: 37124154

Abstract

Purpose

To describe the spatial distribution and morphologic characteristics of macrophage-like cells called hyalocytes in the posterior vitreous cortex of a patient with unilateral partial posterior vitreous detachment (PVD) using coronal plane en face optical coherence tomography (OCT).

Observations

A 54-year-old male with sickle cell disease (HbSC genotype) presented with a partial PVD in one eye. Rendered volumes of a slab extending from 600 μm to 3 μm anterior to the inner limiting membrane (ILM) revealed hyperreflective foci in the detached posterior vitreous cortex suspended anterior to the macula, likely representing hyalocytes. In the fellow eye without PVD, hyperreflective foci were located 3 μm anterior to the ILM. The morphology of the cells in the eye with PVD varied between a ramified state with multiple elongated processes and a more activated state characterized by a plump cell body with fewer retracted processes. In the same anatomical location, the hyperreflective foci were 10-fold more numerous in the patient with vaso-occlusive disease than in an unaffected, age-matched control.

Conclusions and Importance

Direct, non-invasive, and label-free techniques of imaging cells at the vitreoretinal interface and within the vitreous body is an emerging field. The findings from this case report suggest that coronal plane en face OCT can be used to provide a detailed and quantitative characterization of cells at the human vitreo-retinal interface in vivo. Importantly, this case report demonstrates that 3D-OCT renderings can enhance visualization of these cells in relation to the ILM, which may provide clues concerning the identity and contribution of these cells to the pathogenesis of vitreo-retinal diseases.

Keywords: Vitreous, Posterior vitreous detachment, Optical coherence tomography (OCT), OCT angiography, Hyalocytes

1. Introduction

Posterior vitreous detachment (PVD) is the separation of the posterior vitreous cortex from the inner limiting membrane (ILM) of the retina.1 PVD occurs due to weakening of vitreo-retinal adhesion and fibrous liquefaction of gel vitreous, both of which are related to aging. The latter is also found in myopia.2 In some cases, liquefaction occurs without sufficient dehiscence at the vitreo-retinal interface resulting in anomalous PVD, at times with vitreoschisis,3,4 which has been implicated in a variety of vitreo-retinal interface diseases.3,5, 6, 7, 8, 9, 10 Furthermore, vitreoschisis can result in persistence of hyalocytes on the retinal surface, making it difficult to distinguish these from retinal microglia. Thus, there has recently been considerable debate regarding the precise composition of the heterogenous cell populations detected at the human adult vitreo-retinal interface.11,12 Characterizing these cell populations would be beneficial for better understanding their function, their role(s) in disease, and the potential for improved therapies.11, 12, 13, 14

Recent technological advances in clinical optical coherence tomography (OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) have enabled precise and detailed in vivo evaluation of macrophage-like cells, such as microglia and hyalocytes, in the human retina.15, 16, 17 Both imaging modalities have been able to investigate the mobility16 and ramified morphology15 of these cells, qualities that are considered characteristic for macrophages.11 As described by Rajesh et al., microglia reside within the retinal nerve fiber layer and the inner and outer plexiform layers and may play important roles in tissue repair, antigen presentation, and phagocytosis.12 Perivascular macrophages have been found to be a distinct cell population from microglia and are primarily found in the retinal nerve fiber layer, playing an important role in vascular homeostasis and maintenance of the blood-brain barrier.18 Monocyte-derived macrophages are hypothesized to migrate into the retina, including the retinal surface, in response to inflammation.19

Hyalocytes are resident macrophages of the vitreous body and play an essential role in pre-retinal cell proliferation.15, 16, 17,20,21 First described by Hannover et al. in the 1840s, hyalocytes are macrophage-like cells embedded in the dense collagen fibril network of the vitreous base and posterior vitreous cortex at a variable distance anterior to the ILM.3,14,22, 23, 24, 25 Histological studies have confirmed that hyalocytes are macrophages that stain positively for macrophage markers like CD169, Iba-1, and F4/8026 and have the innate ability to undergo changes in morphology, immunophenotype, and density in response to external insults from the retinal micro-environment.16 In disease, these cells promote proliferative vitreo-retinopathy and premacular/epiretinal membrane formation causing macular pucker.5,9,10,13,27 In health, hyalocytes may synthesize and metabolize vitreous hyaluronan,28,29 other extracellular matrix components, and a variety of enzymes, all essential for maintaining transparency and avascularity of the vitreous body.26,30

The following case details the use of clinical en face OCT-R imaging to characterize the morphology and spatial distribution of macrophage-like cells believed to be hyalocytes in the posterior vitreous cortex of a patient who presented with a partial, unilateral PVD. Due to the presence of vaso-occlusive disease in both eyes of the study subject, a healthy age-matched control subject was included for comparison. These evaluations were HIPAA compliant and adhered to the tenets of the Declaration of Helsinki. Written informed consent to publish these images was obtained from both participants included in this report. We demonstrate that three-dimensional reconstruction of OCT volumes can further enhance visualization of these cells. While definitive identification of these cells cannot be conducted without post-mortem tissue analysis with immunohistochemical staining of the cells described herein, their morphological characteristics and spatial distribution supports the hypothesis that these cells constitute resident hyalocytes of the posterior vitreous cortex.14,23, 24, 25

2. Case report

A 54-year-old man with a history of sickle cell disease (HbSC genotype) was compared to a 55-year-old woman as an unaffected control with no known prior history of diabetes, HbSC disease, or retinal pathology. The male subject had a history of hypertension, well-controlled Type 2 Diabetes (glycosylated hemoglobin = 4.7%), multiple vaso-occlusive crises, and hospitalization for acute chest syndrome at age 36. On examination, best corrected visual acuity was 20/20 OD and 20/30 OS. Intraocular pressure was 12 mmHg OD and 14 mmHg OS. Anterior segment exams were unremarkable for both eyes. Dilated fundoscopy revealed a few drusen, venous dilatation, and arteriovenous nicking without any evidence of diabetic retinopathy (Fig. 1, A1 & B1). The electronic medical record system indicated that the patient had stage 4 proliferative sickle cell retinopathy. Enhanced Depth Imaging Spectral Domain OCT (EDI-SDOCT) scans (Spectralis OCT, Heidelberg Engineering Inc., Heidelberg, Germany) centered at the fovea demonstrated a partial PVD OD, still attached to the optic disc, with numerous hyperreflective foci scattered in the posterior vitreous cortex (Fig. 1, A2). In the OS, EDI-OCT scanning centered at the fovea revealed that the posterior vitreous was attached to the ILM (Fig. 1, B2). Foveal OCT scans revealed temporal retinal thinning of both eyes (Fig. 1, A2, B2).

Fig. 1.

Fig. 1

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Color fundus photo and optical coherence tomography (OCT) of both eyes in a patient with sickle cell disease. A1 and B1: Isolated hypopigmented spots, arteriolar narrowing, venous dilatation and arteriovenous nicking are seen in OD. The white square shows the 3 × 3 mm area of the OCT-A/OCT-R coronal plane en face and horizontal black arrow indicates the location of the B-scan in both eyes. A2: Horizontal B-scan at the center of the fovea in OD shows the detached posterior vitreous cortex marked with white arrows. The temporal retina shows marked thinning of the inner layers. B2: Horizontal B-scan centered at the fovea in OS shows no posterior vitreous detachment, but this is not an accurate diagnosis based solely on OCT.31 The temporal retina also demonstrates marked thinning of the inner layers. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

OCT angiography (OCT-A) with matching coronal plane (en face) OCT reflectance (OCT-R) was performed using a commercial spectral domain OCT system with a scan rate of 70,000 A-scans per second, scan beam wavelength centered at 840 nm, and bandwidth of 45 nm (Avanti RTVue-XR; Optovue, Fremont, CA, USA). Each B-scan was composed of 304 A-scans; a total of 608 B-scans per volumetric raster scan was obtained. Spacing between B-scans was 10 μm. Each OCT-R and OCT-A image pair was composed of a merged X-fast and Y-fast volumetric raster scan. The imaging session for both subjects consisted of a set of 10 sequential 3 mm × 3 mm OCT scans centered at the fovea and were approximately 20 minutes in duration each. Following image acquisition, OCT-R and corresponding OCT-A images were generated using the Optovue AngioAnalytics software (version 2017.1.0) and the XR-Avanti Exporting Tool (version 2019.1.28, Optovue).16 While OCT-R images were generated using the mean projection of the reflectance signal, OCT-A images were generated using the split-spectrum amplitude decorrelation angiography algorithm.32 Image registration and averaging were performed using ImageJ (ImageJ, U.S. National Institute of Health, Bethesda, Maryland, USA). Averaging was conducted to minimize motion artifacts and improve signal-to-noise ratio on OCT-R and OCT-A images.32,33 Axial length was obtained using an IOLMaster (Carl Zeiss Meditec, Dublin, CA, USA) for correction of ocular magnification of each averaged image. 3-D rendered OCT-R volumes of the fovea were generated using MIPAV (Medical Image Processing, Analysis, and Visualization, version 10.0.0; US National Institutes of Health, Bethesda, Maryland, USA) and ImageJ 3D Viewer to enhance visualization of hyperreflective foci at the vitreo-retinal interface. In order to quantify the cell density using the averaged 3-μm OCT-R slab and the en face 597 μm slab extending into the vitreous in both subjects, one trained expert manually marked the center of these cells on a 500 μm × 500 μm region of interest (ROI).

In the study subject, averaged OCT-A images demonstrated significant capillary dropout in the supero-temporal region of both eyes of the study subject compared to the unaffected control (Fig. 2A1, 2B1, 2C1). In the study subject's eye without PVD (OS), analysis of the averaged 3 μm OCT-R slab anterior to the ILM at the macula demonstrated clearly discernible hyperreflective foci that were distinctly sparse centrally and exhibited greater densities peripherally (Fig. 2B2). Non-uniform spatial separation of the hyperreflective spots was observed in OS without lateral overlapping. In contrast, there was almost complete absence of hyperreflective foci 3 μm anterior to the ILM in the eye with PVD (OD) (Fig. 2A2). Rendered volumes of a slab extending from 3 μm anterior to the ILM to 600 μm into the vitreous demonstrated the presence of numerous hyperreflective foci in front of the macula in OD (Fig. 2A3, Fig. 3A, Movie 1). These foci were visibly absent in the OCT-R slab extending from 3 μm anterior to the ILM to 600 μm in the eye without PVD (Fig. 2B3, Fig. 3B).

Fig. 2.

Fig. 2

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A1, B1, C1: Full retinal vascular layer OCT-A and coronal -plane en face OCT –R images of the sickle cell disease patient (OU) (A1, B1) compared to a representative eye from the unaffected control (OD (C1). Full retinal vascular layer centered on the fovea shows focal capillary non-perfusion in the supero-temporal quadrant of both eyes with a larger foveal avascular zone in OD (A1, B1). Magnified regions of the red boxes are shown in Fig. 4. A2 and B2: Coronal plane en face OCT-R slab from ILM to 3 μm immediately above the ILM demonstrates few macrophage-like hyalocytes in OD compared to OS, which shows numerous cells scattered anterior to the ILM. A3: Coronal plane en face 597 μm vitreous OCT-R slab above the ILM centered at the fovea of OD revealing a layer of macrophage-like hyalocytes suspended in the vitreous (see also Movie 1). B3: Few cells are observed in the vitreous of OS; marked inner retinal layer thinning is observed at the temporal aspect of the macula. C2 and C3: Minimal hyperreflective foci are visualized on the coronal plane en face 3 μm OCT-R slab above the ILM and the en face 597 μm vitreous OCT-R slab above the ILM centered at the fovea of OD in the unaffected control. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3.

Fig. 3

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3-D rendered macular OCT-R volumes (3 mm × 3 mm x 1 mm). A: Corresponding coronal plane en face 597 μm vitreous OCT-R slab located above the ILM indicates the presence of hyperreflective foci representing macrophage-like hyalcoyteswith various morphologies centered around the fovea of the OD. B: Only few macrophage-like hyalocytes are visible in the en face 597 μm vitreous OCT-R slab in OS.

Supplementary video related to this article can be found at https://doi.org/10.1016/j.ajoc.2023.101836

The following is/are the supplementary data related to this article.

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While the hyperreflective foci were found in a different axial location in each eye of the study subject, their morphological characteristics were noted to be similar, with many characterized as ramified with elongated, filopedia-like processes while others appeared with more amoeboid somata (Fig. 2A3, 2B2, Fig. 4). In contrast, sparse hyperreflective foci were identified both 3 μm anterior to the ILM and in the en face 597 μm slab extending into the vitreous of the unaffected control's eyes, of which representative images are included herein (Fig. 2C2 and 2C3). Manual quantitative analysis revealed that the eye with PVD contained 34 hyperreflective foci/mm2 in the posterior vitreous cortex and 27 hyperreflective foci/mm2 3 μm anterior to the ILM in the eye without PVD. This contrasted sharply with the eyes of the control subject, which had a density of 2 foci/mm2 at a distance 3 μm anterior to the ILM.

Fig. 4.

Fig. 4

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Magnified supero-temporal regions from Fig. 2 of both eyes showing the full vascular layer OCT-A, the en face slabs where the macrophage-like hyalocytes were most densely located and a color overlay of the two images. A1 and B1: Capillary non-perfusion in the supero-temporal quadrant of both eyes. A2: Coronal plane en face 597 μm vitreous OCT-R slab located anterior to the ILM shows the presence of macrophage-like hyalocytes with varying morphologies in the OD (yellow arrows indicate plump, amoeboid morphologies indicating an “activated” state). B2: Coronal plane en face 3 μm OCT-R slab immediately anterior to the ILM shows the presence of macrophage-like hyalocytes with varying morphologies anterior to the ILM surface in the OS (yellow arrows indicate slender, elongated morphology indicating a more “quiescent” state). A3 and B3: Color overlay of macrophage-like hyalocytes in the vitreous OCT-R slab (cyan) and anterior to the ILM surface OCT-R slab (green) superimposed on the corresponding full vascular layer of the OCT-A scans (red) in the OD and OS, respectively (white arrows indicate the location of the same macrophage-like hyalocytes). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

In both eyes of the study subject, the hyperreflective foci appeared randomly distributed, without any predilection for ischemic regions (Fig. 4). Markers have been included in Fig. 4A2, 4B2, 4A3, and 4B3 to indicate the varying morphologies of the macrophage-like cells. The control subject had very few hyperreflective foci located 3 μm above the ILM surface to make possible a comparison with the study subject.

3. Discussion

In this report, we demonstrate the use of clinical en face OCT to characterize the distribution, morphology, and density of macrophage-like cells believed to represent hyalocytes in a patient with a partial PVD in the setting of retinal vaso-occlusive disease. While the precise identity of these cells cannot be definitively deduced from the label-free imaging technique described in this report, we hypothesize that the morphology and spatial distribution of these mostly ramified foci in the vitreous body sufficiently resemble that of hyalocytes as opposed to other monocyte-derived macrophages.

As discussed by Castanos et al., hyalocytes primarily reside within the vitreous body, whereas retinal microglia are primarily found within the nerve fiber layer, inner and outer plexiform layers, and the ganglion cell layer.16 Animal studies in guinea pigs and mice have visualized hyalocytes as being spindle-shaped or amoeboid-shaped cells, closely resembling the morphological characteristics of the cells visualized on OCT in this study and those that were described in Migacz et al.‘s adaptive optics study.16,26,34 Hammer et al. utilized adaptive optics to visualize macrophage-like cells above the ILM with a distinct pattern of distribution similar to that of the cells described in this report.15 Similar to Wang et al., we found a greater density of hyalocytes in the eye with PVD and also found no significant pattern in terms of propensity of these cells to localize to different vascular locations.11 However, in contrast to Wang et al.‘s findings, we hypothesize that the cells visualized in the coronal plane en face 597 μm slab extending into the vitreous body are comprised primarily of hyalocytes. This is because these same cells are not seen within the human retina, a finding that was also reported by Kurokawa's in vivo adaptive optics study.21 Further post-mortem or animal studies with staining are necessary to confirm or refute our hypothesis.

It has been speculated that hyalocytes may become activated into a fibrocyte-like state in the context of mechanically-induced vitreoschisis.17,35,36 Thus, characterizing these cells in subjects with PVD could be a promising biomarker to assess the risk for subsequent vitreo-retinal interface complications, such as formation of premacular membranes causing macular pucker. Hyalocytes have previously been implicated in the pathogenesis of vitreo-retinal interface diseases.22,26,37,38 While some authors such as Wang et al. have hypothesized that retinal microglia and other monocyte-derived macrophages extravasate from the vasculature or from within the retina in response to PVD and the presence of pro-inflammatory mediators such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and vascular endothelial growth factor (VEGF),11 the findings in this case suggest that these cells were already embedded within the posterior vitreous cortex, since they are not visualized within the retina using this same imaging technique. This limitation could potentially have been due to the needle-shaped morphology of foveal glial cells described by Singaravelu et al.39 and to the reduced contrast between the visualized cells and the adjacent retinal tissue on OCT-R. Importantly, the findings in this case indicate the importance of maintaining a high index of suspicion for these cells within the formed vitreous in eyes with PVD and other vitreo-retinal disorders, beyond just looking anterior to the macula, since the posterior vitreous could be detached. When measurements of cells within the vitreous are performed, the presence, or lack thereof, of a PVD and the axial location of the cells should be noted.

The presence of vaso-occlusive disease in our study subject was very likely accompanied by increased levels of pro-inflammatory mediators that are known to influence cellular activity and alter cellular morphology. In vivo visualization studies have reported characteristic morphology of macrophage-like cells located anterior to the ILM, varying from a dendritic appearance in health to cells with retracted processes and an amoeboid shape in disease.15, 16, 17,40, 41, 42 The morphology is believed to be an indicator of immunosurveillance function: a ramified cell shape is associated with a “resting” state whereas an amoeboid morphology is associated with an “inflammatory” state.,16, 17, 43, 44, 45, 46 These studies demonstrated that macrophage-like cells in healthy human retina exhibit regular spatial distribution and ramified morphology with filopedia-like processes anterior to the ILM, equivalent to a dormant state described by Karlstetter et al. and Nimmerjahn et al.47,48 Nimmerjahn et al. also described the nonuniform distribution and spherical somata of activated microglia in response to injury, equivalent to the morphology described by Castanos et al. in patients with proliferative diabetic retinopathy, central retinal vein occlusion, and open angle glaucoma.16 In line with these prior descriptions, we hypothesize that the macrophage-like hyalocytes visualized in the study subject exhibited both quiescent and activated states.

Our hypothesis regarding the identity of the hyerreflective foci visualized in our study subject's vitreous is corroborated by Nimmerjahn et al.‘s finding that only local retinal microglia less than 90 μm apart from the site of injury were observed to migrate and respond to injury.48 While microglial somata were observed to adopt a more spherical configuration in response to injury, indicating an activated state, they were not observed to migrate toward the injured site within the observation period (5.5 hours) if they were greater than 90 μm from the site of injury. On the other hand, immunogenetic studies have shown that hyalocytes residing in the vitreous are capable of selective gene expression in response to local inflammatory stimuli, which can result in various immunologic sequelae such as leukocyte migration, antigen processing, and antigen presentation.37,38,40,41 Notably, Schumann et al. demonstrated that immunoreactivity of hyalocyte markers was most prominent in clusters of cells in ILM specimens obtained from 20 patients, whereas single glial cells were identified in eyes with macular holes.49 Moreover, Schumann et al. found that hyalocytes are uniquely capable of transdifferentiation into myofibroblasts which possess potent contractile properties resulting in tractional forces on the retina. These may contribute to the development of vitreo-retinal interface diseases in the absence of complete separation of the posterior vitreous cortex from the ILM. Similar to Schumann et al.‘s findings, our study subject's eye with PVD exhibited a distinct cell cluster concentrated at the macula, which may suggest some degree of cytokine activation in part due to retinal vaso-occlusive disease unrelated to PVD.

4. Conclusion

Clinical OCT is capable of in vivo imaging macrophage-like cells that are most likely hyalocytes. This imaging modality may be helpful for studying various vitreo-retinal disorders. In this case, three-dimensional renderings of clinical en face OCT-R slabs extending 600 μm into the vitreous body were utilized to visualize hyalocytes along and within the detached posterior vitreous cortex. When evaluating such cells, the presence or absence of PVD and its axial location should be considered. Our findings suggest that macrophage-like hyalocytes may play a role in various vitreo-retinal disorders through their response to pro-inflammatory mediators in the vitreous body, especially in the setting of retinal vascular disease.

Patient consent

Written informed consent was obtained from the patient. This report does not contain any personal information that could lead to patient identification.

Funding

This report was supported by the National Institutes of Health under award numbers R01HL159116 and R01EY027301. Additional funding for this research was provided by the New York Eye and Ear Infirmary Foundation Grant, the Marrus Family Foundation, the Challenge Grant award from Research to Prevent Blindness, and the Jorge N. Buxton Microsurgical Foundation, and the VMR Research Foundation. The sponsors and funding organizations had no role in the design or conduct of this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Authorship

All authors attest that they meet the current ICMJE criteria for Authorship.

SA: Investigation, Data Curation, Writing. HAR: Investigation, Data Curation, Writing. TYC: Supervision, Methodology, Visualization, Writing – Review & Editing, Project Administration, Funding Acquisition. JRG: Writing – Review & Editing, Funding Acquisition. JS: Data Analysis, Writing – Review and Editing, funding acquisition. RBR: Conceptualization, Resources, Writing – Review and editing, Funding acquisition.

Declaration of competing interest

SA (none), HAR (none), and TYC (none).

JRG has the following commercial relationships to disclose: CSL Behring: Code C (Consultant); Novartis: Code C (Consultant).

RBR has the following commercial relationships to declare: Optovue: Code C.

(Consultant); Astellas: Code C; (Consultant); Boehringer-Ingerheim:Code C (Consultant);

CellView: Code C; OD-OS: Code C; Opticology: Code I (Personal Financial Interest);

Regeneron: Code C; Lumithera: Code C (Consultant); Guardion Health: Code C (Consultant);

Bayer: Code C (Consultant); Genentech-Roche: Code C (Consultant).

JS has the following commercial relationships to declare: ALCON Surgical: Code C (Consultant).

Acknowledgements

None.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2023.101836.

Appendix A. Supplementary data

The following are the Supplementary data to this article.

Fig. S1.

Fig. S1

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