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Stem Cells and the Ocular Lens: Implications for Cataract Research and Therapy
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.
... 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. ...
A modified computational model of the human eye was used to obtain and compare different probability density functions, radial profiles of light pattern distributions, and images of the point spread function formed in the human retina under the presence of different kinds of
particles inside crystalline lenses suffering from cataracts. Specifically, this work uses simple particles without shells and multilamellar bodies (MLBs) with shells. The emergence of such particles alters the formation of images on the retina. Moreover, the MLBs change over time,which affects properties such as the refractive index of their shell. Hence, this work not only simulates the presence of such particles but also evaluates the incidence of particle parameters such as particle diameter, particle thickness, and shell refractive index, which are set based on reported experimental values. In addition, two wavelengths (400 nm and 700 nm) are used for light passing through the different layers of the computational model. The effects of these parameters on light scattering are analyzed using the simulation results. Further, in these results, the effects of light scattering on image formation can be seen when single particles, early-stage MLBs, or mature MLBs are incorporated in the model. Finally, it is found that particle diameter has the greatest impact on image formation.
Here we describe a modified method for harvesting tens-of-millions of human lens epithelial-like cells from differentiated pluripotent stem cell cultures. To assess the utility of this method, we analysed the lens cell population via: light microscopy; single cell RNA-sequencing and gene ontology analyses; formation of light-focusing micro-lenses; mass spectrometry; and electron microscopy. Both individually and collectively, the data indicate this simplified harvesting method provides a large-scale source of stem cell-derived lens cells and micro-lenses for investigating human lens and cataract formation.
Purpose:
To estimate the cumulative risk of retinal detachment (RD) after routine cataract surgery by phacoemulsification.
Setting:
Department of Ophthalmology, Aarhus University Hospital, Denmark
Methods:
Retrospective cohort study based on 12.222 consecutive cataract surgeries in 7.856 patients using phacoemulsification over a 6 year period from 2000 to 2005. Cases with a diagnosis of RD were identified through the procedure-coding database at the Medical Registry of Aarhus University Hospital, which is based on Diagnosis Related Groups (DRG) and used to report to the Danish Patients Registry (LPR). For each case the age of the patient, gender, axial length, surgical complications, postoperative Nd:YAG capsulotomy and time interval between cataract surgery and RD were recorded.
Results:
The mean follow-up time was 64.8 months (range 26.2–97.6 months). Forty-eight (48) cases of RD were identified making an overall cumulative risk of 0.39%. As compared to the normal incidence of RD reported in the Scandinavian literature, the relative risk of RD following cataract surgery was about 2.3 times that of the natural incidence. As compared to the average cataract group, the group of RD following cataract surgery was characterized by a younger mean age (60.5 vs. 73.7 years), male gender (58.3% vs 34.8%), longer axial lengths (24.56 vs 23.25 mm) and a higher frequency of surgical complications (10.4% vs 1.8%) (p<0.001) but not a higher frequency of Nd:YAG capsulotomy (p>0.05),
Conclusions:
The cumulative risk of RD after lens surgery was about 2.3 times the natural incidence but seems to be lower than that of older reports.
Synopsis:
Retinal detachment following cataract surgery is associated with young age, male gender, long axial lengths and surgical complications. The cumulative risk of RD after lens surgery was about 2.3 times the natural.
Fibroblast growth factors play a key role in regulating lens epithelial cell proliferation and differentiation via an anteroposterior gradient that exists between the aqueous and vitreous humours. FGF-2 is the most important for lens epithelial cell proliferation and differentiation. It has been proposed that the presentation of FGF-2 to the lens epithelial cells involves the lens capsule as a source of matrix-bound FGF-2. Here we used immunogold labelling to measure the matrix-bound FGF-2 gradient on the inner surface of the lens capsule in flat-mounted preparations to visualize the FGF-2 available to lens epithelial cells. We also correlated FGF-2 levels with levels of its matrix-binding partner perlecan, a heparan sulphate proteoglycan (HSPG) and found the levels of both to be highest at the lens equator. These also coincided with increased levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in lens epithelial cells that localised to condensed chromosomes of epithelial cells that were Ki-67 positive. The gradient of matrix-bound FGF-2 (anterior pole: 3.7±1.3 particles/μm(2); equator: 8.2±1.9 particles/μm(2); posterior pole: 4±0.9 particles/μm(2)) and perlecan (anterior pole: 2.1±0.4 particles/μm(2); equator: 5±2 particles/μm(2); posterior pole: 1.9±0.7 particles/μm(2)) available at the inner lens capsule surface was measured for the bovine lens. These data support the anteroposterior gradient hypothesis and provide the first measurement of the gradient for an important morphogen and its HSPG partner, perlecan, at the epithelial cell-lens capsule interface.
Cataract surgery is one of the oldest and the most frequent outpatient clinic operations in medicine performed worldwide. The clouded human crystalline lens is replaced by an artificial intraocular lens implanted into the capsular bag. During the last six decades, cataract surgery has undergone rapid development from a traumatic, manual surgical procedure with implantation of a simple lens to a minimally invasive intervention increasingly assisted by high technology and a broad variety of implants customized for each patient's individual requirements. This review discusses the major advances in this field and focuses on the main challenge remaining - the treatment of presbyopia. The demand for correction of presbyopia is increasing, reflecting the global growth of the ageing population. Pearls and pitfalls of currently applied methods to correct presbyopia and different approaches under investigation, both in lens implant technology and in surgical technology, are discussed.
Presbyopia, the gradual loss of accommodation that becomes clinically significant during the fifth decade of life, is a physiologic inevitability. Different technologies are being pursued to achieve surgical correction of this disability; however, a number of limitations have prevented widespread acceptance of surgical presbyopia correction, such as optical and visual distortion, induced corneal ectasia, haze, anisometropy with monovision, regression of effect, decline in uncorrected distance vision, and the inherent risks with invasive techniques, limiting the development of an ideal solution. The correction of the presbyopia and the restoration of accommodation are considered the final frontier of refractive surgery. The purpose of this paper is to provide an update about current procedures available for presbyopia correction, their advantages, and disadvantages.
Human nuclear cataract formation is a multi-factorial disease with contributions to light scattering from many cellular sources that change their scattering properties over decades. The aging process produces aggregation of cytoplasmic crystallin proteins, which alters the protein packing and texture of the cytoplasm. Previous studies of the cytoplasmic texture quantified increases in density fluctuations in protein packing and theoretically predicted the corresponding scattering. Multilamellar bodies (MLBs) are large particles with a core of crystallin cytoplasm that have been suggested to be major sources of scattering in human nuclei. The core has been shown to condense over time such that the refractive index increases compared to the adjacent aged and textured cytoplasm. Electron tomography is used here to visualize the 3D arrangement of protein aggregates in aged and cataractous lens nuclear cytoplasm compared to the dense protein packing in the cores of MLBs. Thin sections, 70 nm thick, were prepared from epoxy-embedded human transparent donor lenses and nuclear cataracts. Tilt series were collected on an FEI T20 transmission electron microscope (TEM) operated at 200 kV using 15 nm gold particles as fiducial markers. Images were aligned and corrected with FEI software and reconstructed with IMOD and other software packages to produce animated tilt series and stereo anaglyphs. The 3D views of protein density showed the relatively uniform packing of proteins in aged transparent lens nuclear cytoplasm and less dense packing of aged cataractous cytoplasm where many low-density regions can be appreciated in the absence of the TEM projection artifacts. In contrast the cores of the MLBs showed a dense packing of protein with minimal density fluctuations. These observations support the conclusion that, during the nuclear cataract formation, alterations in protein packing are extensive and can result in pronounced density fluctuations. Aging causes the MLB cores to become increasingly different in their protein packing from the adjacent cytoplasm. These results support the hypothesis that the MLBs increase their scattering with age and nuclear cataract formation.
Our previous studies indicate an important role for fibroblast growth factor (FGF) in lens development. Here we study the expression of the flg variant of FGF receptor 1 (FGFR1) during lens development by immunohistochemistry and in situ hybridisation. FGFR1 was expressed throughout lens development. Prominent FGFR1 immunoreactivity was associated with cell nuclei, particularly in differentiating lens fibres, suggesting internalisation and nuclear translocation of the receptor. FGFR1 immunoreactivity was also associated with basolateral membranes of cells in the equatorial region and at lens sutures. FGFR1 mRNA was only weakly expressed during early lens morphogenesis but expression increased with the onset of lens fibre differentiation. Once the lens acquired its distinct polarity, an anteroposterior gradient in both protein reactivity and mRNA signal was evident. Anteriorly, central epithelial cells showed weak expression for FGFR1, whereas more posteriorly, in the germinative and transitional zones of the lens where cells maximally proliferate and undergo early stages of fibre differentiation, respectively, expression was significantly stronger. The anteroposterior gradient of increased expression of FGFR1 in the lens coincides with the previously documented anteroposterior gradient of FGF stimulation. In lens epithelial explants, FGF stimulation was found to upregulate FGFR1 expression. Such upregulation may be an important mechanism for generating a high level of FGF stimulation and ensuring a fibre differentiation response. In postnatal rat lenses, there was a significant age-related decline in FGFR1 expression; this correlates with the reduced rate of lens fibre differentiation with age. Overall, these studies support the hypothesis that FGF and FGFR1 are important for regulation of lens fibre differentiation throughout lens development. © 1996 Wiley-Liss, Inc.
The signaling pathways and transcriptional effectors responsible for directing mammalian lens development provide key regulatory molecules that can inform our understanding of human eye defects. The hedgehog genes encode extracellular signaling proteins responsible for patterning and tissue formation during embryogenesis. Signal transduction of this pathway is mediated through activation of the transmembrane proteins smoothened and patched, stimulating downstream signaling resulting in the activation or repression of hedgehog target genes. Hedgehog signaling is implicated in eye development, and defects in hedgehog signaling components have been shown to result in defects of the retina, iris, and lens.
We assessed the consequences of constitutive hedgehog signaling in the developing mouse lens using Cre-LoxP technology to express the conditional M2 smoothened allele in the embryonic head and lens ectoderm.
Although initial lens development appeared normal, morphological defects were apparent by E12.5 and became more significant at later stages of embryogenesis. Altered lens morphology correlated with ectopic expression of FoxE3, which encodes a critical gene required for human and mouse lens development. Later, inappropriate expression of the epithelial marker Pax6, and as well as fiber cell markers c-maf and Prox1 also occurred, indicating a failure of appropriate lens fiber cell differentiation accompanied by altered lens cell proliferation and cell death.
Our findings demonstrate that the ectopic activation of downstream effectors of the hedgehog signaling pathway in the mouse lens disrupts normal fiber cell differentiation by a mechanism consistent with a sustained epithelial cellular developmental program driven by FoxE3.
From the most recent data the magnitude of visual impairment and its causes in 2010 have been estimated, globally and by WHO region. The definitions of visual impairment are the current definitions of presenting vision in the International Classification of Diseases version 10.
A systematic review was conducted of published and unpublished surveys from 2000 to the present. For countries without data on visual impairment, estimates were based on newly developed imputation methods that took into account country economic status as proxy.
Surveys from 39 countries satisfied the inclusion criteria for this study. Globally, the number of people of all ages visually impaired is estimated to be 285 million, of whom 39 million are blind, with uncertainties of 10-20%. People 50 years and older represent 65% and 82% of visually impaired and blind, respectively. The major causes of visual impairment are uncorrected refractive errors (43%) followed by cataract (33%); the first cause of blindness is cataract (51%).
This study indicates that visual impairment in 2010 is a major health issue that is unequally distributed among the WHO regions; the preventable causes are as high as 80% of the total global burden.
To examine the association between vitamin C and cataract in the Indian setting.
Population-based cross-sectional analytic study.
A total of 5638 people aged ≥60 years.
Enumeration of randomly sampled villages in 2 areas of north and south India to identify people aged ≥60 years. Participants were interviewed for socioeconomic and lifestyle factors (tobacco, alcohol, household cooking fuel, work, and diet); attended a clinical examination, including lens photography; and provided a blood sample for antioxidant analysis. Plasma vitamin C was measured using an enzyme-based assay in plasma stabilized with metaphosphoric acid, and other antioxidants were measured by reverse-phase high-pressure liquid chromatography.
Cataract and type of cataract were graded from digital lens images using the Lens Opacity Classification System III (LOCS III), and cataract was classified from the grade in the worse eye of ≥4 for nuclear cataract, ≥3 for cortical cataract, and ≥2 for posterior subcapsular cataract (PSC). Any cataract was defined as any unoperated or operated cataract.
Of 7518 enumerated people, 5638 (75%) provided data on vitamin C, antioxidants, and potential confounders. Vitamin C was inversely associated with cataract (adjusted odds ratio [OR] for highest to lowest quartile = 0.61; 95% confidence interval (CI), 0.51-0.74; P=1.1×10(-6)). Inclusion of other antioxidants in the model (lutein, zeaxanthin, retinol, β-carotene, and α-tocopherol) made only a small attenuation to the result (OR 0.68; 95% CI, 0.57-0.82; P < 0.0001). Similar results were seen with vitamin C by type of cataract: nuclear cataract (adjusted OR 0.66; CI, 0.54-0.80; P < 0.0001), cortical cataract (adjusted OR 0.70; CI, 0.54-0.90; P < 0.002), and PSC (adjusted OR 0.58; CI, 0.45-0.74; P < 0.00003). Lutein, zeaxanthin, and retinol were significantly inversely associated with cataract, but the associations were weaker and not consistently observed by type of cataract. Inverse associations were also observed for dietary vitamin C and cataract.
We found a strong association with vitamin C and cataract in a vitamin C-depleted population.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Cataract is a visible opacity in the lens substance, which, when located on the visual axis, leads to visual loss. Age-related cataract is a cause of blindness on a global scale involving genetic and environmental influences. With ageing, lens proteins undergo non-enzymatic, post-translational modification and the accumulation of fluorescent chromophores, increasing susceptibility to oxidation and cross-linking and increased light-scatter. Because the human lens grows throughout life, the lens core is exposed for a longer period to such influences and the risk of oxidative damage increases in the fourth decade when a barrier to the transport of glutathione forms around the lens nucleus. Consequently, as the lens ages, its transparency falls and the nucleus becomes more rigid, resisting the change in shape necessary for accommodation. This is the basis of presbyopia. In some individuals, the steady accumulation of chromophores and complex, insoluble crystallin aggregates in the lens nucleus leads to the formation of a brown nuclear cataract. The process is homogeneous and the affected lens fibres retain their gross morphology. Cortical opacities are due to changes in membrane permeability and enzyme function and shear-stress damage to lens fibres with continued accommodative effort. Unlike nuclear cataract, progression is intermittent, stepwise and non-uniform.
The eye lens is avascular, deriving nutrients from the aqueous and vitreous humours. It is, however, unclear which mechanisms mediate the transfer of solutes between these humours and the lens' fibre cells (FCs). In this review, we integrate the published data with the previously unpublished ultrastructural, dye loading and magnetic resonance imaging results. The picture emerging is that solute transfer between the humours and the fibre mass is determined by four processes: (i) paracellular transport of ions, water and small molecules along the intercellular spaces between epithelial and FCs, driven by Na(+)-leak conductance; (ii) membrane transport of such solutes from the intercellular spaces into the fibre cytoplasm by specific carriers and transporters; (iii) gap-junctional coupling mediating solute flux between superficial and deeper fibres, Na(+)/K(+)-ATPase-driven efflux of waste products in the equator, and electrical coupling of fibres; and (iv) transcellular transfer via caveoli and coated vesicles for the uptake of macromolecules and cholesterol. There is evidence that the Na(+)-driven influx of solutes occurs via paracellular and membrane transport and the Na(+)/K(+)-ATPase-driven efflux of waste products via gap junctions. This micro-circulation is likely restricted to the superficial cortex and nearly absent beyond the zone of organelle loss, forming a solute exchange barrier in the lens.
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.
Growth factors play key roles in influencing cell fate and behaviour during development. The epithelial cells and fibre cells that arise from the lens vesicle during lens morphogenesis are bathed by aqueous and vitreous, respectively. Vitreous has been shown to generate a high level of fibroblast growth factor (FGF) signalling that is required for secondary lens fibre differentiation. However, studies also show that FGF signalling is not sufficient and roles have been identified for transforming growth factor-β and Wnt/Frizzled families in regulating aspects of fibre differentiation. In the case of the epithelium, key roles for Wnt/β-catenin and Notch signalling have been demonstrated in embryonic development, but it is not known if other factors are required for its formation and maintenance. This review provides an overview of current knowledge about growth factor regulation of differentiation and maintenance of lens cells. It also highlights areas that warrant future study.
The lens was the first tissue in which the concept of embryonic induction was demonstrated. For many years lens induction was thought to occur at the time the optic vesicle and lens placode came in contact. Since then, studies have revealed that lens placodal progenitor cells are specified already at gastrula stages, much earlier than previously believed, and independent of optic vesicle interactions. In this review, I will focus on how individual signalling molecules, in particular BMP, FGF, Wnt and Shh, regulate the initial specification of lens placodal cells and the progressive development of lens cells. I will discuss recent work that has shed light on the combination of signalling molecules and the molecular interactions that affect lens specification and proper lens formation. I will also discuss proposed tissue interactions important for lens development. A greater knowledge of the molecular interactions during lens induction is likely to have practical benefits in understanding the causes and consequences of lens diseases. Moreover, knowledge regarding lens induction is providing fundamental important insights into inductive processes in development in general.
Cataracts are often considered to be an unavoidable consequence of aging. Oxidative damage is a major cause or consequence of cortical and nuclear cataracts, the most common types of age-related cataracts.
In this review, we consider the different risk factors, natural history and etiology of each of the 3 major types of age-related cataract, as well as the potential sources of oxidative injury to the lens and the mechanisms that protect against these insults. The evidence linking different oxidative stresses to the different types of cataracts is critically evaluated.
We conclude from this analysis that the evidence for a causal role of oxidation is strong for nuclear, but substantially lower for cortical and posterior subcapsular cataracts. The preponderance of evidence suggests that exposure to increased levels of molecular oxygen accelerates the age-related opacification of the lens nucleus, leading to nuclear cataract. Factors in the eye that maintain low oxygen partial pressure around the lens are, therefore, important in protecting the lens from nuclear cataract.
Maintaining or restoring the low oxygen partial pressure around that lens should decrease or prevent nuclear cataracts.
To assess the association between healthy diet scores and prevalence of nuclear cataract in women.
The association between healthy diet scores, which reflect adherence to the US dietary guidelines, and prevalence of nuclear cataract determined 4 to 7 years later was assessed in a sample of Women's Health Initiative Observational Study participants (aged 50-79 years) residing in Iowa, Wisconsin, and Oregon. Scores on the 1995 Healthy Eating Index, which reflect adherence to 1990 guidelines, were assigned from responses to food frequency questionnaires at the Women's Health Initiative baseline (1994-1998). Presence of nuclear cataract was determined from slitlamp photographs and self-reports of cataract extractions were assessed from May 1, 2001, to January 31, 2004, in 1808 women participating in the Carotenoids in Age-Related Eye Disease Study.
Having a high 1995 Healthy Eating Index score was the strongest modifiable predictor of low prevalence of nuclear cataract among numerous risk factors investigated in this sample. The multivariate-adjusted odds ratio for high vs low quintile for diet score was 0.63 (95% confidence interval, 0.43-0.91). Higher prevalence of nuclear cataract was also associated with other modifiable factors (smoking and marked obesity) and nonmodifiable factors (having brown eyes, myopia, and high pulse pressure). Vitamin supplement use was not related to cataract.
These data add to the body of evidence suggesting that eating foods rich in a variety of vitamins and minerals may contribute to postponing the occurrence of the most common type of cataract in the United States.
The eye lens is an encapsulated avascular organ whose function is to focus light on the retina. Lens comprises a single progenitor cell lineage in multiple states of differentiation. Disruption of lens function leading to protein aggregation and opacity results in age-onset cataract. Cataract is a complex disease involving genetic and environmental factors. Here, we report the development of a new 3-stage system that differentiates human embryonic stem cells (hESCs) into large quantities of lens progenitor-like cells and differentiated 3-dimensional lentoid bodies. Inhibition of BMP signaling by noggin triggered differentiation of hESCs toward neuroectoderm. Subsequent reactivation of BMP and activation of FGF signaling stimulated formation of lens progenitor cells marked by the expression of PAX6 and alpha-crystallins. The formation of lentoid bodies was most efficient in the presence of FGF2 and Wnt-3a, yielding approximately 1000 lentoid bodies/30-mm well. Lentoid bodies expressed and accumulated lens-specific markers including alphaA-, alphaB-, beta-, and gamma-crystallins, filensin, CP49, and MIP/aquaporin 0. Collectively, these studies identify a novel procedure to generate lens cells from hESCs that can be applied for studies of lens differentiation and cataractogenesis using induced pluripotent stem (iPS) cells derived from various cataract patients.
Even though zebrafish development does not include the formation of a lens vesicle, the authors' hypothesis is that the processes of cell differentiation are similar in zebrafish and mammals and determine cell fates in the lens.
Two-photon live embryo imaging was used to follow individual fluorescently labeled cells in real-time from the placode stage at 16 hours postfertilization (hpf) until obvious morphologic differentiation into epithelium or fiber cells had occurred at approximately 28 hpf. Immunohistochemistry was used to label proliferating, differentiating, and apoptotic cells.
Similar to the mammal, cells in the teleost peripheral lens placode migrated to the anterior lens mass and differentiated into an anterior epithelium. Cells in the central lens placode migrated to the posterior lens mass and differentiated into primary fiber cells. Anterior and posterior polarization in the zebrafish lens mass was similar to mammalian lens vesicle polarization. Primary fiber cell differentiation was apparent at approximately 21 hpf, before separation of the lens from the surface ectoderm, as evidenced by cell elongation, exit from the cell cycle, and expression of Zl-1, a marker for fiber differentiation. TUNEL labeling demonstrated that apoptosis was not a primary mechanism for lens separation from the surface ectoderm.
Despite the absence of a lens vesicle in the zebrafish embryo, lens organogenesis appears to be well conserved among vertebrates. Results using three-dimensional live embryo imaging of zebrafish development showed minimal differences and strong similarities in the fate of cells in the zebrafish and mammalian lens placode.
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.
Although more than 1 million cataract surgeries are performed annually in the United States, little is known about the frequency of use or cost of various services provided in connection with this procedure. To assess the frequency with which various ophthalmic, optometric, anesthesia, and medical services are provided in conjunction with cataract surgery and to estimate the cost to Medicare associated with those services, we analyzed 1985 through 1988 Medicare claims records of a nationally representative 5% sample of Medicare beneficiaries. The experience of 57 103 Medicare beneficiaries who underwent extracapsular cataract surgery in 1986 or 1987 that was not combined with another ophthalmologic procedure formed the basis of our analysis. Projections for current costs were performed using 1991 charges allowed by Medicare for physician services. We estimate that the median charge allowed by Medicare for a "typical" episode of cataract surgery in 1991 was approximately $2500. In addition to the $3.4 billion that Medicare spent in 1991 on such "typical" episodes, Medicare spent more than $39 million on miscellaneous "atypical" preoperative ophthalmologic tests, such as specular microscopy (14% of cases) and potential acuity testing (8% of cases), more than $7 million on postoperative ophthalmologic diagnostic tests, such as fluorescein angiography (3% of cases), and more than $18 million on perioperative medical services (most commonly electrocardiography and chest roentgenography). The major determinants of the cost to Medicare associated with cataract surgery are the rate of performance of cataract surgery and neodymium-YAG laser capsulotomy and the charges allowed for these procedures. Many other ophthalmologic and medical services are often provided preoperatively and/or postoperatively, but total Medicare expenditures for these services are relatively small.
To outline the refractive problems associated with presbyopia and to review the basis and relative merits of currently-available methods for their correction, with detailed consideration of spectacle and contact lens approaches.
In the developed world, most of the present population will spend roughly half their lives as presbyopes. The well-known presbyopic changes with age in amplitude of accommodation and required near addition are briefly reviewed, together with the less widely acknowledged slow drifts that occur in distance refraction. The desirability of restoring to presbyopes clear vision for objects at any distance, ideally corresponding to vergences within the range of at least 0 to -5 D, in any viewing direction, is stressed. A general outline is given of possible corrective methods. Methods which satisfy the needs of a 50 year-old may not be suitable for the 80 year-old. Corrections may involve both fixed- and variable-focus lens systems, and surgical methods which modify the optics of the cornea, replace the crystalline lens with different fixed optics, or attempt to at least partially restore active accommodation. Some more recent methods of spectacle and contact lens correction are described in more detail. Particular attention is given to recent commercially-developed spectacles in which the corrective power can be varied actively by either mechanical (liquid-filled deformable lenses or Alvarez lenses) or electrical (liquid crystal lenses) means to allow objects at different distances to be seen clearly. Contact lens corrections show less progress and are still preferred only by a minority of older patients, most of whom are early presbyopes.
The rising proportion of presbyopes in the population, covering an age span of around 40 years, represents both a problem for those concerned with giving their patients the best vision possible at both far and near viewing distances and a commercial opportunity. Traditional single-vision distance and near, bifocal, and progressive spectacle lens solutions, together with contact lens modalities for presbyopic correction, are being challenged by a variety of new approaches. It remains to be seen whether the latter will receive wide acceptance in practice.
Human embryonic stem cells (hESCs) provide a powerful tool to investigate early events occurring during human embryonic development. In the present study, we induced differentiation of hESCs in conditions that allowed formation of neural and non-neural ectoderm and to a lesser extent mesoderm. These tissues are required for correct specification of the neural plate border, an early embryonic transient structure from which neural crest cells (NCs) and cranial placodes (CPs) originate. Although isolation of CP derivatives from hESCs has not been previously reported, isolation of hESC-derived NC-like cells has been already described. We performed a more detailed analysis of fluorescence-activated cell sorting (FACS)-purified cell populations using the surface antigens previously used to select hESC-derived NC-like cells, p75 and HNK-1, and uncovered their heterogeneous nature. In addition to the NC component, we identified a neural component within these populations using known surface markers, such as CD15 and FORSE1. We have further exploited this information to facilitate the isolation and purification by FACS of a CP derivative, the lens, from differentiating hESCs. Two surface markers expressed on lens cells, c-Met/HGFR and CD44, were used for positive selection of multiple populations with a simultaneous subtraction of the neural/NC component mediated by p75, HNK-1, and CD15. In particular, the c-Met/HGFR allowed early isolation of proliferative lens epithelium-like cells capable of forming lentoid bodies. Isolation of hESC-derived lens cells represents an important step toward the understanding of human lens development and regeneration and the devising of future therapeutic applications.
Purpose of review:
To describe the development and use of intraocular lenses (IOLs) as drug delivery systems and to review the current literature on their application and efficacy.
Recent findings:
Many drugs have been loaded onto IOLs by coating or by attachment in a separate reservoir. With incorporation of polymeric materials either as a coating or by attachment as a separate reservoir, it is possible to achieve a sustained and controlled release of drugs. Experimental evidence in animal models has shown that IOL drug delivery systems are effective in the prevention and treatment of inflammation, infection and posterior capsule opacification after cataract surgery.
Summary:
The use of IOLs as drug delivery reservoirs appears to show great promise. Although excellent results with therapeutic potential have been reported in experimental animal studies, further studies are needed to reach clinical use.
The lens of 6-day-old normal mouse was implanted into the lentectomized eye of adult mouse to examine the effect of retina upon the growth of the implanted lens in vivo. The implanted lens grew normally and its transparency was kept for more than 5 months after implantation. The connection between the implanted lens and the ciliary part of the recipient iris was well established with the regeneration of zonular fibers from the recipient. In young lenses implanted reversely into adult eyes, the epithelial cells facing the retina elongated and a new epithelium was formed on the corneal side of the lens within 5 days. Young lenses implanted either in normal or reverse orientation into eyes from which the retina was previously removed did not grow. The cells of the original lens epithelium of these lenses were randomly accumulated beneath the posterior lens capsule, while the anterior portion of the implanted lenses became an epithelial structure without cell elongation. These results suggest that the growth of the implanted lens may be dependent on the retina of the adult eye.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.