Insights into the biochemical and biophysical mechanisms mediating the longevity of the transparent optics of the eye lens

Quinlan, Roy A.; Clark, John I.

doi:10.1016/j.jbc.2022.102537

Cited by 21 publications

(50 citation statements)

References 390 publications

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“…This hypothesis has been described recently as "cataractogenic load". [2] Our results support that 𝛽-crystallins are a critical aspect of the crystallin network, therefore we suggest that age-related modifications of 𝛽crystallins should be investigated more closely in future discussions. For now, the lessons gleaned from our in vitro analysis provide an important breakthrough in modeling crowding of a lens.…”

Section: Discussionsupporting

confidence: 79%

“…Despite nearly two centuries of research on the vertebrate lens, [1][2] the molecular mechanisms underlying proper lens function, i.e., transparency, and ultimate dysfunction, i.e., cataractogenesis, are still not fully understood. Present at DOI: 10.1002/advs.202303279 concentrations up to 400 mg mL −1 , [3][4][5] crystallins make up roughly 90% of the total soluble protein content in the lens which is delicately balanced by short-range ordering via weak and non-covalent interactions to maintain transparency.…”

Section: Introductionmentioning

confidence: 99%

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Design and Characterization of Model Systems that Promote and Disrupt Transparency of Vertebrate Crystallins In Vitro

Bergman,

Hernandez,

Deffler

et al. 2023

Advanced Science

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Positioned within the eye, the lens supports vision by transmitting and focusing light onto the retina. As an adaptive glassy material, the lens is constituted primarily by densely‐packed, polydisperse crystallin proteins that organize to resist aggregation and crystallization at high volume fractions, yet the details of how crystallins coordinate with one another to template and maintain this transparent microstructure remain unclear. The role of individual crystallin subtypes (α, β, and γ) and paired subtype compositions, including how they experience and resist crowding‐induced turbidity in solution, is explored using combinations of spectrophotometry, hard‐sphere simulations, and surface pressure measurements. After assaying crystallin combinations, β‐crystallins emerged as a principal component in all mixtures that enabled dense fluid‐like packing and short‐range order necessary for transparency. These findings helped inform the design of lens‐like hydrogel systems, which are used to monitor and manipulate the loss of transparency under different crowding conditions. When taken together, the findings illustrate the design and characterization of adaptive materials made from lens proteins that can be used to better understand mechanisms regulating transparency.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Design and Characterization of Model Systems that Promote and Disrupt Transparency of Vertebrate Crystallins In Vitro

Bergman,

Hernandez,

Deffler

et al. 2023

Advanced Science

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“…For cataracts, it may be possible that there are several etiologically different subtypes, e.g., early onset PSC cataracts with evident threshold (e.g., attributable to excess LEC proliferation), late onset PSC cataracts with no clear threshold (e.g., attributable to LEC cell death and inactivation), and late onset cortical or nuclear cataracts with no clear threshold (e.g., attributable to the increased cataractogenic load that accelerates age-related changes) (Fig. 2) ( 89 , 105 , 105 , 296 ). For DCS, existence or otherwise of threshold dose for DSC in aggregate and each subtype is unclear, and mechanisms should vary among subtypes much more than cataracts.…”

Section: Future Perspectivesmentioning

confidence: 99%

Noncancer Effects of Ionizing Radiation Exposure on the Eye, the Circulatory System and beyond: Developments made since the 2011 ICRP Statement on Tissue Reactions

Hamada

2023

Radiation Research

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For radiation protection purposes, noncancer effects with a threshold-type dose-response relationship have been classified as tissue reactions (formerly called nonstochastic or deterministic effects), and equivalent dose limits aim to prevent occurrence of such tissue reactions. Accumulating evidence demonstrates increased risks for several late occurring noncancer effects at doses and dose rates much lower than previously considered. In 2011, the International Commission on Radiological Protection (ICRP) issued a statement on tissue reactions to recommend a threshold of 0.5 Gy to the lens of the eye for cataracts and to the heart and brain for diseases of the circulatory system (DCS), independent of dose rate. Literature published thereafter continues to provide updated knowledge. Increased risks for cataracts below 0.5 Gy have been reported in several cohorts (e.g., including in those receiving protracted or chronic exposures). A dose threshold for cataracts is less evident with longer follow-up, with limited evidence available for risk of cataract removal surgery. There is emerging evidence for risk of normal-tension glaucoma and diabetic retinopathy, but the long-held tenet that the lens represents among the most radiosensitive tissues in the eye and in the body seems to remain unchanged. For DCS, increased risks have been reported in various cohorts, but the existence or otherwise of a dose threshold is unclear. The level of risk is less uncertain at lower dose and lower dose rate, with the possibility that risk per unit dose is greater at lower doses and dose rates. Target organs and tissues for DCS are also unknown, but may include heart, large blood vessels and kidneys. Identification of potential factors (e.g., sex, age, lifestyle factors, coexposures, comorbidities, genetics and epigenetics) that may modify radiation risk of cataracts and DCS would be important. Other noncancer effects on the radar include neurological effects (e.g., Parkinsonŉs disease and dementia) of which elevated risk has increasingly been reported. These late occurring noncancer effects tend to deviate from the definition of tissue reactions, necessitating more scientific developments to reconsider the radiation effect classification system and risk management. This paper gives an overview of historical developments made in ICRP prior to the 2011 statement and an update on relevant developments made since the 2011 ICRP statement.

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“…The eye organoids are excellent examples of tissue–tissue coupling, including biomechanical and bioelectrical interactions, vascularization, innervation, host–microbiome interactions, as well as circadian clock entrainment [ 5 , 455 ]. The ocular lens further represents a system with an intricate and compartmentalized microcirculation system and different basic metabolisms, external biomechanical properties, and most importantly, transparency and light refraction [ 456 ]. There are challenges of how to mimic these functions; nevertheless, the existing and expanding tool warehouse provides an integrated framework to adapt synergistic engineering modalities to reconstruct all these components in next-generation lentoid bodies, e.g., “bioengineered 3D lenses” or “light-focusing human micro-lenses” [ 427 ], and complex eye organoids [ 5 ].…”

Section: Conclusion and Future Research Directionsmentioning

confidence: 99%

Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology

Cvekl

Camerino

2022

Cells

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In vitro differentiation of human pluripotent stem cells (hPSCs) into specialized tissues and organs represents a powerful approach to gain insight into those cellular and molecular mechanisms regulating human development. Although normal embryonic eye development is a complex process, generation of ocular organoids and specific ocular tissues from pluripotent stem cells has provided invaluable insights into the formation of lineage-committed progenitor cell populations, signal transduction pathways, and self-organization principles. This review provides a comprehensive summary of recent advances in generation of adenohypophyseal, olfactory, and lens placodes, lens progenitor cells and three-dimensional (3D) primitive lenses, “lentoid bodies”, and “micro-lenses”. These cells are produced alone or “community-grown” with other ocular tissues. Lentoid bodies/micro-lenses generated from human patients carrying mutations in crystallin genes demonstrate proof-of-principle that these cells are suitable for mechanistic studies of cataractogenesis. Taken together, current and emerging advanced in vitro differentiation methods pave the road to understand molecular mechanisms of cataract formation caused by the entire spectrum of mutations in DNA-binding regulatory genes, such as PAX6, SOX2, FOXE3, MAF, PITX3, and HSF4, individual crystallins, and other genes such as BFSP1, BFSP2, EPHA2, GJA3, GJA8, LIM2, MIP, and TDRD7 represented in human cataract patients.

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Insights into the biochemical and biophysical mechanisms mediating the longevity of the transparent optics of the eye lens

Cited by 21 publications

References 390 publications

Design and Characterization of Model Systems that Promote and Disrupt Transparency of Vertebrate Crystallins In Vitro

Design and Characterization of Model Systems that Promote and Disrupt Transparency of Vertebrate Crystallins In Vitro

Noncancer Effects of Ionizing Radiation Exposure on the Eye, the Circulatory System and beyond: Developments made since the 2011 ICRP Statement on Tissue Reactions

Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology

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