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Noninvasive in vivo imaging of embryonic ?-cell development in the anterior chamber of the eye.

ABSTRACT: The fetal environment plays a decisive role in modifying the risk for developing diabetes later in life. Developing novel methodology for noninvasive imaging of ?-cell development in vivo under the controlled physiological conditions of the host can serve to understand how this environment affects ?-cell growth and differentiation. A number of culture models have been designed for pancreatic rudiment but none match the complexity of the in utero or even normal physiological environment. Speier et al. recently developed a platform of noninvasive in vivo imaging of pancreatic islets using the anterior chamber of the eye where islets get vascularized, grow and respond to physiological changes. The same methodology was adapted for the study of pancreatic development. E13.0, still undifferentiated rudiments with fluorescent lineage tracing were implanted in the AC of the eye, allowing the longitudinal study of their growth and differentiation. Within 48 h the anlages get vascularized and grow but their mesenchyme displays a selective growth advantage. The resulting imbalance leads to alteration in the differentiation pattern of the progenitors. Reducing the mesenchyme to its bare minimum before implantation allows the restoration of a proper balance and a development that mimics the normal pancreatic development. These groundbreaking observations demonstrate that the anterior chamber of the eye provides a good system for noninvasive in vivo fluorescence imaging of the developing pancreas under the physiology of the host and can have important implications for designing strategies to prevent or reverse the deleterious effects of hyperglycemia on altering ?-cell function later in life.

SUBMITTER: Cras-Meneur C

PROVIDER: S-EPMC4878273 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Noninvasive in vivo imaging of embryonic β-cell development in the anterior chamber of the eye.

Cras-Méneur Corentin C Elghazi Lynda L Fort Patrice P Bernal-Mizrachi Ernesto E

Islets 20160301 2

The fetal environment plays a decisive role in modifying the risk for developing diabetes later in life. Developing novel methodology for noninvasive imaging of β-cell development in vivo under the controlled physiological conditions of the host can serve to understand how this environment affects β-cell growth and differentiation. A number of culture models have been designed for pancreatic rudiment but none match the complexity of the in utero or even normal physiological environment. Speier e ...[more]

PMID: 26950054

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Project description:ImportanceExfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.ObjectiveTo determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.Design, setting, and participantsA 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.ExposuresRare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.Main outcomes and measuresThe primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.ResultsThe discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.Conclusions and relevanceIn this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.

Project description:PurposeWe sought to investigate anatomic mechanisms of angle narrowing by assessing ocular biometric determinants of anterior chamber angle width.DesignPopulation-based cross-sectional study.MethodsSubjects ≥50 years of age from the Chinese American Eye Study underwent a comprehensive ocular examination, including anterior segment optical coherence tomography imaging and ultrasound A-scan. Independent variables, including anterior chamber depth (ACD), lens vault (LV), iris curvature (IC), anterior chamber width, lens thickness, vitreous cavity depth, and axial length, and dependent variables, including angle opening distance, were measured in 1 randomly selected eye per subject. Univariable and multivariable regression models with standardized regression coefficients (SRCs) and semipartial correlation coefficients squares (SPCC2) were used to assess relative and unique contributions by independent variables to angle width.ResultsTwo thousand two hundred twenty-five subjects (1433 women and 834 men) were included in the analysis. All biometric parameters except lens thickness differed between men and women (age-adjusted P < .001). In model 1A (R2 = 0.66), which included ACD, lens thickness, and vitreous cavity depth, ACD (SRC = 0.64, SPCC2 = 0.19) and IC (SRC = -0.26, SPCC2 = 0.041) were the strongest determinants of angle opening distance. In model 1B (R2 = 0.58), which included LV and axial length, LV (SRC = -0.46, SPCC2 = 0.1) and IC (SRC = -0.3, SPCC2 = 0.047) were the strongest determinants of angle opening distance. Determinants of angle width were similar in separate multivariable models for men and women.ConclusionsACD, LV, and IC are the strongest determinants of angle width in Chinese Americans. Sex-related differences in angle width are explained by differences among biometric measurements. These results provide insights into anatomic mechanisms of angle narrowing and have important implications for quantitative assessments of angle closure eyes.

Dataset Information

Noninvasive in vivo imaging of embryonic ?-cell development in the anterior chamber of the eye.

Publications

Noninvasive in vivo imaging of embryonic β-cell development in the anterior chamber of the eye.

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