Elsevier

Micron

Volume 43, Issue 7, July 2012, Pages 759-781
Micron

Invited Review
Ultrastructure of the human retina in aging and various pathological states

https://doi.org/10.1016/j.micron.2012.01.011Get rights and content

Abstract

Vision is hampered in aging and diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and glaucoma. This review collates the fine structural alterations of the human retina in aging and various pathological situations and their links to the disease pathogenesis. It transpires that most changes occur at the level of the retinal pigment epithelium –Bruch's membrane and the photoreceptor layer, causing visual problems to the sufferers. These changes include loss of normal, essential features of these cells and their gradual disappearance. It is important to understand in depth the selective vulnerability of this retinal region to alterations in aging and diseases. Evidence indicates that some of these changes may be mediated by the effects of oxidative stress, inflammation, and chronic light exposure. There are changes also in the inner retinal layers, wherein hypertension, auto-immunity, hypoxia and ischemia could play significant roles in disease pathogenesis. Results of extensive research utilizing animal models have broadened our idea about photoreceptor pathology. However, equivalent knowledge on various changes in aging human retina and in dystrophies that affect the macula is not complete. Since cone photoreceptor and ganglion cell death are a potential problem, it is imperative to know about the basic facts on how they are affected and the mechanisms involved in their death. Thus, prevention of cone and ganglion cell loss should be the target of choice. This review also highlights the significant role played by electron microscopy in understanding such ultrastructural changes and future strategies utilizing it and other techniques to fill some of the existing lacunae and advance our knowledge.

Highlights

► We examined ultrastructural changes in the human retina with aging and in diseases. ► Photoreceptor cells and the pigment epithelium alter significantly in both situations. ► The pigment epithelium-Bruch's membrane interface changes in many diseases. ► The inner retinal cells and blood vessels alter significantly in ischemia and injury. ► Animal models may provide answers to some of the existing problems of retinal diseases.

Introduction

The advent of electron microscopy in biological research has been one of the greatest achievements of mankind. Besides its seminal contribution in the discovery of cellular organelles in the early part of the twentieth century, it has given a new dimension in understanding the fine structural features of various cells and tissues in normal state and in development and their deviations in pathological state. Since then electron microscopy has been routinely employed to see the fine structure of the retinal photoreceptor cells (Sjöstrand, 1953a, Sjöstrand, 1953b, Sjöstrand, 1958, De Robertis, 1956, Yamada, 1957, Ladman, 1958) and retinal pigment epithelium (RPE; Bairati and Orzalesi, 1963) to understand the mechanism of photoreception and associated phenomena, such as shedding and renewal of photoreceptor outer segment discs (Bairati and Orzalesi, 1963, Young, 1967, Young, 1976, Ishikawa and Yamada, 1969, Young and Bok, 1969, Bok and Hall, 1971, LaVail et al., 1972, Steinberg et al., 1980), anatomical association between the RPE and photoreceptor outer segments (Steinberg et al., 1977), phagocytosis of shed outer segment discs (Hogan et al., 1974, Anderson et al., 1978, Bok and Young, 1979) and route of newly synthesized protein transport into photoreceptor outer segments (Papermaster et al., 1985). Later on, it assumed a new role in elucidating the structural alterations of cells in various inherited retinal diseases in animals, axonal regeneration, light-induced photoreceptor degeneration, synaptic plasticity, retinal cell transplantation and recently in human aging and age-related retinal diseases. This review highlights the major known facts on the ultrastructural changes of the human retina in aging and various pathological situations, the role played by transmission electron microscopy (TEM) and immunogold electron microscopy (IEM) in understanding them and comments on the future research employing TEM and IEM to know some of the existing issues with human retinal pathology.

Section snippets

General plan of the mammalian retina

The mammalian retina, like that of other vertebrates, is constructed of 10 different layers (Polyak, 1941, Polyak, 1957, Rodieck, 1973; Fig. 1, human), each containing one or more morphological type of neurons specialized for processing of visual information. It is known to contain approximately 55 separate neuronal types (Masland, 2001). The neurons are organized in four layers, the bacillary layer (containing photoreceptor outer and inner segments), the outer nuclear layer (ONL), containing

The macular photoreceptors are susceptible to alterations in aging and pathology

Morphologically, the macular photoreceptors are unique in several aspects; they are extremely long and thin in the foveal center (the central bouquet; Polyak, 1941 Hendrickson and Yuodelis, 1984), allowing them to be accommodated with greater packing density in this specialized retinal region. Only cones (Fig. 2B) are present in the foveola. Outside the foveola, rods first appear (along with cones) in the foveal slope in the parafovea, wherein each cone is surrounded by a row of rods, while in

The inner nuclear layer (INL)

The INL consists of three classes of neurons (horizontal, bipolar and amacrine cells) and one class of macroglial cells, MC. In the foveal center, only the ONL and the fiber layer of Henle are present; the inner retinal layers [INL to nerve fiber layer (NFL)] are displaced laterally away from the foveal center. Bipolar cells are abundant in the INL and their dendrites form synapses with photoreceptors and horizontal cells in the OPL, while their axons synapse with amacrine and ganglion cells in

Vascular changes

The inner retina is nourished by branches of the central retinal vessels. Anatomical findings indicated a restricted blood supply at the macula, the vessels are clearly absent in the foveola and appear densely in parafoveal and perifoveal regions (Iwasaki and Inomata, 1986, Provis et al., 1995). The vessels ramify until they reach the outer margin of the INL; the outer retina with the photoreceptor layer is avascular and derives its nutrition from the choriocapillaris (Rodieck, 1973). Retinal

Changes after traumatic retinal injury

The retina has a delicate cellular organization and suffers from damage in accidents resulting from sports, road-traffic driving and physical abuse of the globes. Blunt ocular non-perforating injuries cause severe histopathological changes to the retina, especially the photoreceptors (Lee, 2001). In traumatic injury resulting from accidental road-traffic accident, the retina shows hemorrhagic lesions in the ONL and INL (Fig. 16A). There is evidence for the presence of pyknotic nuclei in the ONL

Involvement of retina glia in aging and diseases

Human retina contains astrocytes and microglia. The former are mainly distributed in the NFL and GCL, whereas microglia can be found also in outer retina. One study reported astroglial loss with aging of the human retina and astroglial hypertrophy in AMD, the hypertrophied cells showed capacity of phagocytizing dead ganglion cells (Ramírez et al., 2001). Whereas microglia are normally present in the inner retinal layers, in diseased retina they often migrate to the outer retina. In the inner

Impact of aging changes of photoreceptor cells on vision

Aging associates visual deficits in elderly humans, especially at the level of acuity, accommodation, dark adaptation and contrast sensitivity (Spear, 1993). It is also associated with increased incidence of ocular diseases, like AMD, in which there is reported loss of photoreceptor, bipolar and ganglion cells (Gao and Hollyfield, 1992, Curcio et al., 1993, Curcio et al., 1996, Aggarwal et al., 2007). However, photoreceptor submicroscopic changes that occur with normal aging may also have an

Future research

Nowadays, clinical researchers use non-invasive imaging techniques such as optical coherence tomography (and its improved variants) to diagnose the in vivo retinal changes in different diseases and in patients with confirmed mutations to particular genes. TEM played and continues to play a significant role in understanding ultrastructural pathogenesis in postmortal aging and diseased retinal samples. However, novel data can be obtained from using other techniques in combination with TEM to gain

Acknowledgements

The study was carried out following the tenets of the Declaration of Helsinki and approved by the Institute research ethics committee (IHEC approval no. A-01: 02/05/2005; A-59/24.03. 2008 and As-207/2008). We appreciate the gestures of all relatives of the donors who provided with written consent for our use of the donor eyes in research. We thank the authorities of the National Eye Bank, especially to Prof. Radhika Tandon, Dr Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS for providing

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