Differential Responses of Neural Retina Progenitor Populations to Chronic Hyperglycemia.

Nicole Schmitner,Christina Recheis,Jakob Thönig,Robin A Kimmel

doi:10.3390/cells10113265

Abstract

Diabetic retinopathy is a frequent complication of longstanding diabetes, which comprises a complex interplay of microvascular abnormalities and neurodegeneration. Zebrafish harboring a homozygous mutation in the pancreatic transcription factor pdx1 display a diabetic phenotype with survival into adulthood, and are therefore uniquely suitable among zebrafish models for studying pathologies associated with persistent diabetic conditions. We have previously shown that, starting at three months of age, pdx1 mutants exhibit not only vascular but also neuro-retinal pathologies manifesting as photoreceptor dysfunction and loss, similar to human diabetic retinopathy. Here, we further characterize injury and regenerative responses and examine the effects on progenitor cell populations. Consistent with a negative impact of hyperglycemia on neurogenesis, stem cells of the ciliary marginal zone show an exacerbation of aging-related proliferative decline. In contrast to the robust Müller glial cell proliferation seen following acute retinal injury, the pdx1 mutant shows replenishment of both rod and cone photoreceptors from slow-cycling, neurod-expressing progenitors which first accumulate in the inner nuclear layer. Overall, we demonstrate a diabetic retinopathy model which shows pathological features of the human disease evolving alongside an ongoing restorative process that replaces lost photoreceptors, at the same time suggesting an unappreciated phenotypic continuum between multipotent and photoreceptor-committed progenitors.

Highlights

IntroductionDiabetic retinopathy (DR) is the leading cause of vision loss in working-age adults [1], and the global burden of visual impairment and blindness attributable to DR was projected to rise to 3.2 million affected people in 2020 [2]
In pdx1 Mutants, Mutants, Photoreceptor Degeneration Is Not Accompanied by Signs of Acute
To determine whether hyperglycemia-induced suppression of proliferation contributes to the reduced photoreceptor cell numbers, we examined proliferation by injecting EdU into fish aged 3, 6 and 10 mpf, and harvested the eyes two days later

Summary

Introduction

Diabetic retinopathy (DR) is the leading cause of vision loss in working-age adults [1], and the global burden of visual impairment and blindness attributable to DR was projected to rise to 3.2 million affected people in 2020 [2]. Neural tissues such as the brain and retina depend entirely on glucose as the major fuel driving energy metabolism [3]. The blood–retinal barrier maintains a stable milieu even during changing plasma glucose concentrations. When plasma glucose is pathologically high over prolonged periods of time, as in diabetes, these regulatory mechanisms are disrupted. The retina becomes extremely vulnerable to tissue damage, as is manifested in diabetic retinopathy [4]

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