- 作者: Ehsan Ranaei Pirmardan, Yuanlin Zhang, Aliaa Barakat, Marzieh Naseri, Christoph Russmann & Ali Hafezi-Moghadam
- 作者服務機構: 1.Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA 2.Health Campus Göttingen/University of Applied Sciences and Arts (HAWK), Anna-Strasse 25, 37075, Göttingen, Germany 3.Molecular Biomarkers Nano-Imaging Laboratory (MBNI), Brigham and Women’s Hospital, and Department of Radiology, Harvard Medical School, 75 Francis St., Thorn Research Building, Boston, MA, 02115, USA
- 中文摘要:
- 英文摘要:
Background This work elucidates the frst cellular and molecular causes of cataractogenesis. Current paradigm
presupposes elevated blood glucose as a prerequisite in diabetic cataractogenesis. Novel evidence in our model of
diabetic cataract challenges this notion and introduces immune cell migration to the lens and epithelial-mesenchy‑
mal transformation (EMT) of lens epithelial cells (LECs) as underlying causes.
Methods Paucity of suitable animal models has hampered mechanistic studies of diabetic cataract, as most studies
were traditionally carried out in acutely induced hyperglycemic animals. We introduced diabetic cataract in the Nile
grass rat (NGR) that spontaneously develops type 2 diabetes (T2D) and showed its closeness to the human condition.
Specialized stereo microscopy with dual bright-feld illumination revealed novel hyperrefective dot-like microlesions
in the inner cortical regions of the lens. To study immune cell migration to the lens, we developed a unique in situ
microscopy technique of the inner eye globe in combination with immunohistochemistry.
Results Contrary to the existing paradigm, in about half of the animals, the newly introduced hyper refective dot-like
microlesions preceded hyperglycemia. Even though the animals were normoglycemic, we found signifcant changes
in their oral glucose tolerance test (OGTT), indicative of the prediabetic stage. The microlesions were accompanied
with signifcant immune cell migration from the ciliary bodies to the lens, as revealed in our novel in situ microscopy
technique. Immune cells adhered to the lens surface, some traversed the lens capsule, and colocalized with apoptotic
nuclei of the lens epithelial cells (LECs). Extracellular degradations, amorphous material accumulations, and changes
in E-cadherin expressions showed epithelial-mesenchymal transformation (EMT) in LECs. Subsequently, lens fber
disintegration and cataract progression extended into cortical, posterior, and anterior subcapsular cataracts.
Conclusions Our results establish a novel role for immune cells in LEC transformation and death. The fact that
cataract formation precedes hyperglycemia challenges the prevailing paradigm that glucose initiates or is necessary
for initiation of the pathogenesis. Novel evidence shows that molecular and cellular complications of diabetes start
during the prediabetic state. These results have foreseeable ramifcations for early diagnosis, prevention and develop‑
ment of new treatment strategies in patients with diabetes. - 中文關鍵字:
- 英文關鍵字: s Diabetic complications, Polyol pathway, Paradigm shift, Insulin resistance