Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007

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For instance, the loss of photoreceptor cells can be limited to the macula or begin in the periphery and eventually extend to the entire retina. The most common type of retinal degeneration is age-related macular degeneration, which is limited to the central retina and occurs predominantly in older individuals. Hereditary forms of central retinal degeneration also exist and typically have an earlier age of onset. Some examples include Stargardt’s Disease, Best’s Disease, cone dystrophy, pattern dystrophy, and Malattia Leventinese. Macular degenerations are characterized by a loss of central vision and a decreased ability to discriminate fine details. The peripheral visual field and scotopic vision usually remain intact. Symptoms, however, vary greatly in severity between conditions and from one individual to another. As a general rule, these diseases cause significant visual impairment but rarely progress to complete blindness.

Hereditary retinal degenerations that involve the entire retina tend to be more severe. The most common types of these diseases are retinitis pigmentosa (RP) and Usher syndrome. RP is the name given to a group of retinal degenerative diseases with a gradual progression of scotopic symptoms, often occurring over many years or decades. The rods are the first cells to be affected in RP; thus, one of the earliest symptoms is night blindness followed by a progressive loss of peripheral vision leading to “tunnel vision.” Although the majority of patients with RP do not suffer from other neurological deficits, hearing loss can occur in some patients. The combination of RP and congenital hearing impairment is known as Usher syndrome.

Whatever the subtype, retinal degenerative diseases share a common trait—they cannot be cured with existing therapies. In this context, the transplantation of stem cells to the degenerating retina provides a promising strategy for replacing dead cells with new ones, including the potential to integrate with remaining host circuitry and restore the transmission of visual information to the brain.

RETINAL TRANSPLANTATION: FROM PAST TO PRESENT

Retinal transplantation was first performed in 1946 by Tansley who demonstrated features of retinal differentiation in embryonic ocular tissue when transplanted into the brains of young rat (1). The fact that the graft was transplanted into the brain and not the eye did not detract from the momentous discovery that embryonic ocular tissue had the capacity to undergo retinal differentiation even in an ectopic site. Later in 1959, Royo and Quay described the first intraocular retinal transplantation procedure which demonstrated that fetal retina could survive in the anterior chamber of the maternal parent (2).

However, significant interest in the field of retinal transplantation was not generated until the mid-1980s when it was shown that retinal grafts could survive when transplanted into various sites within the eye such as the anterior chamber (3) or the subretinal space (4). It was discovered that graft survival could be enhanced by using a younger donor (5). However, it was also shown that very young donors (early in embryogenesis) yielded less well-organized transplants, implying that there could be a critical period for retinal development (6). Thus, the late fetal period was suggested as the optimal age of tissue for retinal transplantation.

All of these earlier experiments involved transplantation of full-thickness retina. Although transplants remained ordered and viable, they showed a limited ability to

integrate with the host retina. Dissociated retinal microaggregates and retinal cell suspensions were subsequently tried by several investigators (7–9). These microaggregate suspensions were easily introduced into the subretinal space with minimal trauma but were shown to form rudimentarily differentiated rosettes rather than well-organized layers (9,10).

Following this pioneering work, intact photoreceptor sheets were proposed as a more suitable tissue for transplantation. Photoreceptor sheets were first successfully harvested using a vibratome to section gelatin-embedded retinal tissue (11). Subsequently, excimer laser ablation was used by several investigators for the preparation of photoreceptor sheets (12). Although the harvesting of photoreceptor sheets is technically more challenging, it does appear to minimize the problem of rosette formation.

The motivation for using photoreceptor grafts is that the visual pathway downstream of the photoreceptor layer often remains functional, even in advanced retinal degenerations. However, it is now clear that after photoreceptor cells are lost, the remaining outer aspect of the retina reorganizes and eventually resembles a glial scar (13). Nonetheless, the neural retina remains viable, the optic nerve and secondary connections to the visual cortex remain functional, and the visual cortex too, remains intact. This suggests that photoreceptor replacements alone might be sufficient to restore vision in the diseased eye, at least prior to the late-occurring cellular reorganization of the retina.

Several animal studies have suggested that transplanted retinal cells may be able to form synapses and integrate anatomically with host retinal tissue (14–19). The functional capability of the grafted tissues has also been demonstrated via ectopic electrophysiological responses (20) and light-dependent shifts in phototransduction proteins in photoreceptor cells (21). However, functional integration and host visual improvement after transplantation into the eye have been less well established.

In contrast to intraocular grafts, intracranial transplantations have proven to be successful in terms of functional integration with the host. McLoon et al. (1982) showed that embryonic retinal grafts transplanted into the brain of newborn rats established projections to the superior colliculus, demonstrating that a degree of neural plasticity is present in the mammalian visual system beyond the normal period of development of the visual pathways (22). Researchers in the Lund laboratory later demonstrated that retinal transplants were able to establish functional connectivity in the brain by driving a pupillary reflex via the pretectum and that the magnitude of this response reflected the strength of graft-host integration (23–25).

Although transplantation of retinal cells has shown some encouraging results in animals, it is not yet a treatment available for use in humans. In human studies, transplantation of intact sheets of photoreceptor cells (26) or retinal microaggregates (27) into the subretinal space of adults with RP has not yielded reproducible evidence of improved visual function. Retinal cell transplantation is still in its preliminary stages of investigation in the laboratory. The good news, however, is that studies have thus far found that when photoreceptor cells are transplanted to the retina of animals, some features of normal photoreceptors are either maintained within the graft or develop after transplantation. Such studies have shown that transplanted photoreceptors, either in the form of cell suspensions (28) or intact retinal sheets (11,29), display good survival and morphologic

preservation in the host. Transplants of embryonic retinal sheets showed apparent fusion of the graft’s inner plexiform layer (which tends to lose ganglion cells) and the host’s remnant inner nuclear layer (INL). In addition, grafted retinas are able to maintain an organized photoreceptor layer with outer segments that contact the host RPE. Photoreceptors of intact retinal sheets were also shown to have functional phototransduction properties after transplantation into the host. Unfortunately, the grafted photoreceptors and retinal sheets showed limited integration with the host neural retina, precluding downstream transmission of neural signals to the INL.

The lack of anatomical or functional integration of grafted photoreceptors with the host has been attributed to an inherent lack of plasticity in these “mature” donor neurons. Recent studies have shown that although retinal grafts derived from postnatal mice express many markers characteristic of mature retina (e.g., rhodopsin, conventional protein kinase Cα), very few of the grafted cells migrate into, or extend neurites into, the host retina when transplanted into the eyes of mature rd mice (30). Conversely, brain progenitor cells (BPCs) transplanted into the subretinal space of rd mice readily migrate into, and integrate with, the host retina but showed very limited ability to differentiate into mature retinal neurons (30). Therefore, although mature retinal neurons have the ability to potentially restore function to the diseased retina because of their expression of retinal-specific markers, they appear to be resistant to integration within the host. On the other hand, whereas progenitor cells possess the plasticity to migrate and integrate with the host, they do not necessarily differentiate into retinal neurons following transplantation.

This dichotomy of graft-host integration exhibited by mature neurons and neural progenitor cells (NPCs) has led to research aimed at achieving three goals:

(1) improving the integration of whole retinal grafts or photoreceptor sheets, (2) enhancing the ability of progenitor cells to differentiate into functional mature neurons, and (3) using progenitor cells to enhance graft-host integration.

Although there is not yet conclusive evidence that retinal progenitor cell (RPC) transplants result in long-term improved or restored vision in animals or humans with a retinal degeneration, research done thus far demonstrates that the intrinsic multipotentiality and plasticity of progenitor cells offers great potential because RPCs are proliferative, multipotent cells that give rise to postmitotic progeny that ultimately differentiate into the various cell types that comprise the retina, these cells may be the ideal candidates for replacing cells lost to disease. Although NPCs from the retina or brain (RPCs or BPCs) present a promising future approach for treating retinal degenerative diseases, there are still a number of significant obstacles to be surmounted in the coming years.

STEM CELL CHARACTERISTICS

Stem cells are multipotent, self-renewing cells that sit at the top of a lineage hierarchy and proliferate to form differentiated cell types of a given tissue in vivo. In adult organisms, stem cells can divide repeatedly to replenish a tissue or may be quiescent, as in the mammalian retina. Within their niche, stem cells can divide symmetrically to expand their numbers (self-renewing) or undergo asymmetric division to yield both stem cells and committed precursors.

Fig. 1. Schematic of stem cell fate and differentiation.

Not all stem cells are created equal (Fig. 1). The potential for stem cells to differentiate into mature, specialized cells changes as an embryo develops. Stem cells can be:

•Totipotent: In the early stages after fertilization, the stem cells in a dividing zygote are considered totipotent. These cells can form any type of cell, and by definition must be able to generate a complete, viable organism with placenta.

•Pluripotent: Several days after fertilization, the cells of the developing embryo lose “totipotency” and are then considered pluripotent. These cells give rise to the three embryonic germ cell layers and can form any kind of cell found in adults, but can no longer give rise to a complete organism.

•Multipotent: Eventually, the progeny of pluripotent stem cells become multipotent stem cells—the type found in adults. Multipotent stem cells can no longer develop into all or most cell types. Instead, they are limited in terms of cell lineages and can typically develop into certain cell types within a specific tissue, organ, or system. Multipotent stem cells play an important role later in development and replenish the senescent or damaged cells in adult tissue.

Multipotent stem cells exist in many tissues and organs of the body, such as the brain, retina, liver, muscles, cornea, and bone marrow. In recent years, these multipotent stem cells have been isolated and cultured in vitro from different parts of the mammalian retina (31–34). However, in most adult mammals these retinal stem cells (RSCs) remain quiescent and do not mobilize in response to injury. Hence, significant injuries are not repaired and functions lost through neuronal cell death are not regained. In contrast, lower vertebrates such as amphibians, birds, and fish respond to injury by neuronal regeneration. The cellular source for regeneration differs for each class: the RPE in amphibians and embryonic birds, Müller glia in post-hatch birds and intrinsic stem cells in fish as described in a recent review by Hitchcock et al. (35).