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Stem Cells and the Ocular Lens: Implications for Cataract Research and Therapy

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Abstract

A transparent and pliable lens is critical for good quality vision, effective motor and social development, life-long education and employment, and high quality of life. As individuals live beyond the age of 40 they experience progressive lens hardening, called presbyopia, that results in impaired vision due to a reduced ability to accommodate (i.e. to change focus between near and far objects). Due to its age of onset most people, at least in the developed world, will live roughly half their lives dealing with the vision-impairing consequences of presbyopia. Additionally, tens of millions of people have low vision or blindness due to the formation of lenticular opacities, called cataracts, that reduce lens transparency. Due to population ageing, age-related cataracts are becoming an increasing problem worldwide. Thus presbyopia and age-related cataracts are causing, and will increasingly cause, large social and economic hardship across the globe. While decades of research have provided some understanding of the molecular mechanisms that underpin these blinding conditions, new research and clinical therapies are needed to better treat these extensive, costly and life-altering conditions. Advances in stem cell research and technology provide a real opportunity to identify and develop these much-needed new therapies.

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... Although cataracts have caused nearly 50% of cases of blindness worldwide [1,2], the efforts to reduce this disease have not been sufficient and hence cataracts have become an international health concern [3]. The crystalline lens, posterior to the iris and anterior to the vitreous body and retina, has the ability to change the focus between near and far objects [4,5]. Therefore, any change in the refractive index can potentially be the origin of opacity or clouding. ...
... Moreover, the nuclear cataract formation process is slow, gradual, and immutable [5,10]. The refractive index that makes the lens transparent is achieved by the expression and accumulation of crystallin proteins such as α−, β-, and γcrystallins [4]. Hence, any alteration of the structure or composition of the lens can lead to opacity or clouding. ...
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Book
The eye is a complex sensory organ, which enables visual perception of the world. Thus the eye has several tissues that do different tasks. One of the most basic aspects of eye function is the sensitivity of cells to light and its transduction though the optic nerve to the brain. Different organisms use different ways to achieve these tasks. In this sense, eye function becomes a very important evolutionary aspect as well. This book presents the different animal models that are commonly used for eye research and their uniqueness in evaluating different aspects of eye development, evolution, physiology and disease. * Presents information on the major animal models used in eye research including invertebrates and vertebrates * Provides researchers with information needed to choose between model organisms * Includes an introductory chapter on the different types of eyes, stressing possible common molecular machinery.
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Embryonic stem cells have the potential to give rise to all cell lineages when introduced into the early embryo. They also give rise to a limited number of different cell types in vitro in specialized culture systems. In this study, we established a culture system in which a structure consisting of lens, neural retina, and pigmented retina was efficiently induced from embryonic stem cells. Refractile cell masses containing lens and neural retina were surrounded by retinal pigment epithelium layers and, thus, designated as eye-like structures. Developmental processes required for eye development appear to proceed in this culture system, because the formation of the eye-like structures depended on the expression of Pax6, a key transcription factor for eye development. The present culture system opens up the possibility of examining early stages of eye development and also of producing cells for use in cellular therapy for various diseases of the eye. Developmental Dynamics 228:664–671, 2003. © 2003 Wiley-Liss, Inc.
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Crystallins have evolved by various mechanisms that are associated with high expression of their genes in the eye lens. The diversity and pattern of crystallins among different species indicate that independent events have occurred at the molecular level during the evolution of the lens in different invertebrates (jellyfish, squid, and octopus) and vertebrates. Although it is possible that different crystallins are needed to fulfill the specific needs of individual species, the unexpectedly large array of proteins that function as crystallins and their abundance in the lens raise the possibility that selective pressures optimizing the function of certain transcription factors in the lens contribute to the recruitment of crystallins. © 1993 wiley-Liss, Inc.
Article
The refractive power of a lens is determined largely by its surface curvatures and the refractive index of its medium. These properties can also be used to control the sharpness of focus and hence the image quality. One of the most effective ways of doing this is with a gradient index. Eye lenses of all species, thus far, measured, are gradient index (GRIN) structures. The index gradation is one that increases from the periphery of the lens to its centre but the steepness of the gradient and the magnitudes of the refractive index vary so that the optics of the lens accords with visual demands. The structural proteins, the crystallins, which create the index gradient, also vary from species to species, in type and relative distribution across the tissue. The crystallin classes do not contribute equally to the refractive index, and this may be related to their structure and amino acid content. This article compares GRIN forms in eye lenses of varying species, the relevance of these forms to visual requirements, and the relationship between refractive index and the structural proteins. Consideration is given to the dynamics of a living lens, potential variations in the GRIN form with physiological changes and the possible link between discontinuities in the gradient and growth. Finally, the property of birefringence and the characteristic polarisation patterns seen in highly ordered crystals that have also been observed in specially prepared eye lenses are described and discussed.
Article
FGF-3, originally named int-2, was discovered as an oncogene frequently activated in mammary carcinomas resulting from the chromosomal integration of the mouse mammary tumor virus (MMTV). Int-2 was later designated FGF-3 based on sequence homology with other members of the fibroblast growth factor (FGF) family. FGF-1 is the prototypical member of the FGF family, and is the only family member which activates all known FGF receptor isoforms. Transgenic mice expressing in the lens a form of FGF-1 engineered to be secreted show premature differentiation of the entire lens epithelium. In contrast, transgenic mice engineered to secrete FGF-2 in the lens do not undergo premature differentiation of the lens epithelium (C. M. Stolenet al.,1997,Development124, 4009–4017). To further assess the roles of FGFs and FGF receptors in lens development, the αA-crystallin promoter was used to target expression of FGF-3 to the developing lens of transgenic mice. The expression of FGF-3 in the lens rapidly induced epithelial cells throughout the lens to elongate and to express fiber cell-specific proteins including MIP and β-crystallins. This premature differentiation of the lens epithelium was followed by the degeneration of the entire lens. Since FGF-1 and FGF-3 can both activate one FGF receptor isoform (FGFR2 IIIb) that is not activated by FGF-2, these results suggest that activation of FGFR2 IIIb is sufficient to induce fiber cell differentiation throughout the lens epitheliumin vivo.Furthermore, transgenic lens cells expressing FGF-3 were able to induce the differentiation of neighboring nontransgenic lens epithelial cells in chimeric mice. Expression of FGF-3 in the lens also resulted in developmental alterations of the eyelids, cornea, and retina, and in the most severely affected transgenic lines, the postnatal appearance of intraocular glandular structures.
Article
The mammalian lens exhibits characteristic antero-posterior patterns of cellular proliferation, movement and fibre differentiation. Based on our findings that fibroblast growth factor (FGF) induces proliferation, migration and differentiation in a similar sequence as its concentration is increased, we put forward the hypothesis that normal lens morphology with its antero-posterior patterns of cellular behaviour is determined by an antero-posterior gradient of FGF stimulation.Support for this hypothesis is now available from a wide range of studies, including: studies of the distribution of FGF and its mRNA in the eye and FGF activity in ocular media and the lens; studies of FGF receptor and mRNA expression in the lens; and studies of transgenic mice with altered patterns of FGF expression, which exhibit abnormal patterns of differentiation. Furthermore, gross abnormalities in lenses of transgenic mice that express a dominant-negative FGF receptor provide strong evidence that FGF is involved in the differentiation and maintenance of lens fibre cells in situ. Other biological molecules that may modulate the effects of FGF on lens cells in the normal lens have also been investigated, including capsule heparan sulphate proteoglycans, insulin and IGF and TGFβ. In addition, a potential role for TGFβ in the aetiology of cataracts has been identified.It is now clear that there are many possible mechanisms by which the behaviour of lens cells may be regulated to ensure normal growth and maintenance of polarity in the mammalian lens. Although several growth factors are probably involved, a key role for FGF has emerged.
Article
All people will be presbyopic by age 50, and we now understand something of the basis for this condition. It turns out to be a direct consequence of two features; first the design of the transparent lens and the way it must change shape to enable focussing by the human eye, and second the instability of proteins over a very long time period. The incremental changes that take place in the lens to render the central region inflexible by middle age and, as a consequence the person presbyopic, may also promote the subsequent development of cataract. Based on the most recent data, heat-induced denaturation of proteins in the lens appears to be a worthy topic for future investigation. Understanding such processes may allow us to glimpse the origin both of presbyopia and age-related nuclear cataract.
Article
The main aim of this study was to determine whether the neural retina brought about the qualitative changes in protein synthesis associated with lens fibre differentiation. Explants of lens epithelium from newborn rats which only contain α-crystallin in detectable amounts were cultured alone or on pieces of neural retina. In the latter case the explants increased in size and contained α-, β-, and γ-crystallins. This size increase and change in crystallin composition is characteristic of lens fibre differentiation from epithelial cells. To determine if this was a specific property of the neural retina the epithelium was grown on other tissues. Corneal stroma and cartilage brought about some differentiation in the presence of foetal calf serum but were not as effective as the neural retina. Dermis had no effect on differentiation of the lens epithelium. One interpretation of these results is that the neural retina simply provides a good substratum on which the epithelium can grow and differentiate. However, epithelial explants grown in retina-conditioned medium also differentiate. Therefore the explant response must be a result of the modification of the medium by the neural retina.
Article
The pattern of DNA synthesis in the epithelium and the annular pad was studied during development and growth of the chick lens. Cell populations in the inner and the middle regions of the annular pad progressively enter the terminal cell cycle during development. DNA-synthesizing cells gradually become localized in the peripheral epithelium and in the outer region of the annular pad. DNA synthetic activity decreases rapidly in the central region of the lens epithelium. Analysis of the cell numbers suggests that the central epithelial cell population gradually enters a stationary phase. This phenomenon, coupled with progressive localization of cell replication in the peripheral epithelium and the outer region of the annular pad, establishes a specific growth pattern.
Article
Lens explant cultures were used to assess the mechanism of drug-induced cataractogenic potential of NVS001, a peroxisome proliferator-activated receptor delta (PPARδ) agonist, which resulted in cataract in all treated animals during a 13-week rat study. Ciglitazone, a PPARγ agonist and cataractogenic compound, was used as a positive control to validate this model. Rat lenses were extracted and cultured in medium supplemented with antibiotics for 24-h preincubation pretreatment. Lenses showing no signs of damage at the end of the preincubation pretreatment period were randomized into five experimental groups, (1) untreated control, (2) 0.1% dimethyl sulphoxide control, (3) 10μM NVS001, (4) 10μM ciglitazone, and (5) 10μM acetaminophen (negative control). Lenses were treated every 24 h after preincubation pretreatment for up to 48 h. Samples for viability, histology, and gene expression profiling were collected at 4, 24, and 48 h. There was a time-dependent increase in opacity, which correlated to a decrease in viability measured by adenosine triphosphate levels in NVS001 and ciglitazone-treated lenses compared with controls. NVS001 and ciglitazone had comparable cataractogenic effects after 48 h with histology showing rupture of the lens capsule, lens fiber degeneration, cortical lens vacuolation, and lens epithelial degeneration. Furthermore, no changes were seen when lenses were treated with acetaminophen. Gene expression analysis supported oxidative and osmotic stress, along with decreases in membrane and epithelial cell integrity as key factors in NVS001-induced cataracts. This study suggests that in vitro lens cultures can be used to assess cataractogenic potential of PPAR agonists and to study/understand the underlying molecular mechanism of cataractogenesis in rat.
Article
To discuss the development of presbyopia-correcting intraocular lenses (IOLs), what we have learned since their introduction a few decades ago, what are the options currently on the market, and where the technology is heading in the future. Multifocal and accommodating IOLs have gone through several modifications to improve distance, intermediate and near vision compared to their predecessors. These modifications have also targeted unwanted side-effects such as glare and halos in the multifocal lenses and inconsistent near-vision results in the accommodating IOLs and although the results have improved, they are far from perfect. Therefore, careful patient selection for each of these technologies is crucial for success and patient satisfaction. Presbyopia correction remains a great challenge in cataract and refractive surgery. In this article, we review the development of presbyopia-correcting IOLs, starting from the simple, two-zone, multifocal, refractive models introduced 2 decades ago, the current Food and Drug Administration (FDA) approved multifocal and accommodating lenses as well as those undergoing FDA trials and take a look into developing technologies that may be available to us in the future.
Article
Lenses from 27 human eyes ranging in age from 10 to 87 years were used to determine how accommodation and age affect the optical properties of the lens. A scanning laser technique was used to measure focal length and spherical aberration of the lenses, while the lenses were subjected to stretching forces applied through the ciliary body/zonular complex. The focal length of all unstretched lenses increased linearly with increasing age. Younger lenses were able to undergo significant changes in focal length with stretching, whereas lenses older than 60 years of age showed no changes in focal length with stretching. These data provide additional evidence for predominantly lens-based theories of presbyopia. Further, these results show that there are substantial optical changes in the human lens with increasing age and during accommodation, since both the magnitude and the sign of the spherical aberration change with age and stretching. These results show that the optical properties of the older presbyopic lens are quite different from the younger, accommodated lens.
Article
The programmed removal of organelles from differentiating lens fibre cells contributes towards lens transparency through formation of an organelle-free zone (OFZ). Disruptions in OFZ formation are accompanied by the persistence of organelles in lens fibre cells and can contribute towards cataract. A great deal of work has gone into elucidating the nature of the mechanisms and signalling pathways involved. It is apparent that multiple, parallel and redundant pathways are involved in this process and that these pathways form interacting networks. Furthermore, it is possible that the pathways can functionally compensate for each other, for example in mouse knockout studies. This makes sense given the importance of lens clarity in an evolutionary context. Apoptosis signalling and proteolytic pathways have been implicated in both lens fibre cell differentiation and organelle loss, including the Bcl-2 and inhibitor of apoptosis families, tumour necrosis factors, p53 and its regulators (such as Mdm2) and proteolytic enzymes, including caspases, cathepsins, calpains and the ubiquitin-proteasome pathway. Ongoing approaches being used to dissect the molecular pathways involved, such as transgenics, lens-specific gene deletion and zebrafish mutants, are discussed here. Finally, some of the remaining unresolved issues and potential areas for future studies are highlighted.
Article
Unlabelled: PURPOSE OR REVIEW: To conduct a concise review of primary research articles over the preceding year on the subject of the consequences of waiting for cataract surgery. Recent findings: Waiting for cataract surgery beyond 6 months may result in increasing vision loss, decrease in quality life, loss of driver's license, depression and adverse events including falls and fractures. The consequences of waiting for cataract surgery not only affect patients, families and surgeons, but also health ministries and public health policy makers. Consequences are both quantitative and qualitative in nature, ranging from progressive vision loss to patients' decrease in quality of life from factors other than vision loss. Cataract wait lists are not unique to North America, and numerous international articles have described a broad variety of consequences. Summary: Consequences of waiting for cataract surgery are multivariate in nature and easily extend beyond the clinical setting into sociodemographic realms and public health costs and policy arenas.
Article
To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of age-related cataract in a large cohort of men. In a randomized, double-masked, placebo-controlled trial, 11,545 apparently healthy US male physicians 50 years or older without a diagnosis of cataract at baseline were randomly assigned to receive 400 IU of vitamin E or placebo on alternate days and 500 mg of vitamin C or placebo daily. Incident cataract responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review. Long-term use of vitamin E and C supplements has no appreciable effect on cataract. After 8 years of treatment and follow-up, 1174 incident cataracts were confirmed. There were 579 cataracts in the vitamin E-treated group and 595 in the vitamin E placebo group (hazard ratio, 0.99; 95% confidence interval, 0.88-1.11). For vitamin C, there were 593 cataracts in the treated group and 581 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14). Long-term alternate-day use of 400 IU of vitamin E and daily use of 500 mg of vitamin C had no notable beneficial or harmful effect on the risk of cataract. clinicaltrials.gov Identifier: NCT00270647.
Article
  The aim was to determine world-wide patterns of fitting contact lenses for the correction of presbyopia.   Up to 1,000 survey forms were sent to contact lens fitters in each of 38 countries between January and March every year over five consecutive years (2005 to 2009). Practitioners were asked to record data relating to the first 10 contact lens fittings or refittings performed after receiving the survey form.   Data were received relating to 16,680 presbyopic (age 45 years or older) and 84,202 pre-presbyopic (15 to 44 years) contact lens wearers. Females are over-represented in presbyopic versus pre-presbyopic groups, possibly reflecting a stronger desire for the cosmetic benefits of contact lenses among older women. The extent to which multifocal and monovision lenses are prescribed for presbyopes varies considerably among nations, ranging from 79 per cent of all soft lenses in Portugal to zero in Singapore. There appears to be significant under-prescribing of contact lenses for the correction of presbyopia, although for those who do receive such corrections, three times more multifocal lenses are fitted compared with monovision fittings. Presbyopic corrections are most frequently prescribed for full-time wear and monthly replacement.   Despite apparent improvements in multifocal design and an increase in available multifocal options in recent years, practitioners are still under-prescribing with respect to the provision of appropriate contact lenses for the correction of presbyopia. Training of contact lens practitioners in presbyopic contact lens fitting should be accelerated and clinical and laboratory research in this field should be intensified to enhance the prospects of meeting the needs of presbyopic contact lens wearers more fully.
Article
Lens regeneration among vertebrates is basically restricted to some amphibians. The most notable cases are the ones that occur in premetamorphic frogs and in adult newts. Frogs and newts regenerate their lens in very different ways. In frogs the lens is regenerated by transdifferentiation of the cornea and is limited only to a time before metamorphosis. On the other hand, regeneration in newts is mediated by transdifferentiation of the pigment epithelial cells of the dorsal iris and is possible in adult animals as well. Thus, the study of both systems could provide important information about the process. Molecular tools have been developed in frogs and recently also in newts. Thus, the process has been studied at the molecular and cellular levels. A synthesis describing both systems was long due. In this review we describe the process in both Xenopus and the newt. The known molecular mechanisms are described and compared.
Article
Teratogens, substances that may cause fetal abnormalities during development, are responsible for a significant number of birth defects. Animal models used to predict teratogenicity often do not faithfully correlate to human response. Here, we seek to develop a more predictive developmental toxicity model based on an in vitro method that utilizes both human embryonic stem (hES) cells and metabolomics to discover biomarkers of developmental toxicity. We developed a method where hES cells were dosed with several drugs of known teratogenicity then LC-MS analysis was performed to measure changes in abundance levels of small molecules in response to drug dosing. Statistical analysis was employed to select for specific mass features that can provide a prediction of the developmental toxicity of a substance. These molecules can serve as biomarkers of developmental toxicity, leading to better prediction of teratogenicity. In particular, our work shows a correlation between teratogenicity and changes of greater than 10% in the ratio of arginine to asymmetric dimethylarginine levels. In addition, this study resulted in the establishment of a predictive model based on the most informative mass features. This model was subsequently tested for its predictive accuracy in two blinded studies using eight drugs of known teratogenicity, where it correctly predicted the teratogenicity for seven of the eight drugs. Thus, our initial data shows that this platform is a robust alternative to animal and other in vitro models for the prediction of the developmental toxicity of chemicals that may also provide invaluable information about the underlying biochemical pathways.
Article
To investigate the longitudinal subjective and objective visual functional results in adult cataract patients younger than 65 years at surgery. To evaluate the 10-year cumulative incidence of neodymium-yttrium-aluminum-garnet (Nd:YAG) laser treatment. A prospective, longitudinal, population-based cohort study. The study comprised 116 patients younger than 65 years who had cataract surgery during 1 year at Norrlands University Hospital, Umeå, Sweden. Most patients (94%) had received implantation with a hydrophobic acrylic intraocular lens. Evaluated were visual acuity (VA) and visual function questionnaire (VF-14) results before and after surgery. A comparison with patients 65 years or older at surgery was made. Ten years later, 102 survivors were offered eye examinations and again asked to fill out the questionnaire. Past Nd:YAG laser treatment, as well as high- and low-contrast VA results, were analyzed. Ten years postoperatively, 37% of the patients under 65 at surgery had been treated with Nd:YAG in comparison to 20% of the older patients. The cumulative incidence for not having Nd:YAG over 10 years was 72% for those under 65 and 85% for the patients 65 years or more at surgery. Eighteen percent of the younger patients had lost more than 0.1 logarithm of the minimal angle of resolution (logMAR) units of the operated eye, compared with 37% of the older (P = .00003). A reduction in VF-14 score of 10 points or more was found in 9% of the younger and 28% of the older cataract surgery patients (P = .00004). Ten years after surgery, subjective and objective visual function remained stable in most patients younger than 65 years at surgery. More than one-third had received a posterior capsulotomy. Only a few patients with posterior capsular opacification requiring Nd:YAG were untreated at the 10-year follow-up.