Pathological processes in aqueous humor due to iris atrophy predispose to early corneal graft failure in humans and mice
Pathological processes in aqueous humor due to iris atrophy predispose to early corneal graft failure in humans and mice
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DOI：
10.1126/sciadv.aaz5195
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发表时间：
2020-05-01
期刊：
影响因子：
13.6
通讯作者：
Shimazaki, Jun
中科院分区：
文献类型：
--
作者：
Yamaguchi, Takefumi;Higa, Kazunari;Shimazaki, Jun
角膜移植后角膜内皮细胞（CEnC）丢失是移植失败的主要原因，也是临床需要克服的挑战。从长期临床结果中积累的知识表明，房水中蛋白质水平升高与CEnC丢失有关。然而，驱动蛋白和分子过程的全谱仍有待确定。在这里，我们使用多组学分析定义了角膜移植临床结果较差的人类房水样本的体细胞微环境景观和细胞反应，并阐明了特定的驱动改变，包括补体激活和能量稳态紊乱。这些驱动改变也在一种新的小鼠房水模型中得到证实，该模型自发发生虹膜萎缩，导致CEnC丢失。在人类样本中进行的整合多组学应用于新型小鼠模型将有助于开发角膜移植后CEnC缺失患者的治疗模式。
Corneal endothelial cell (CEnC) loss after corneal transplantation is the major cause of graft failure and remains a clinically relevant challenge to overcome. Accumulated knowledge derived from long-term clinical outcomes suggested that elevated protein levels in the aqueous humor are associated with CEnC loss. However, the full spectrum of driver proteins and molecular processes remains to be determined. Here, we defined the somatic microenvironmental landscape and cellular response across human aqueous humor in samples with poor corneal transplantation clinical outcomes using multiomics analyses and clarified specific driver alterations, including complement activation and disturbed energy homeostasis. These driver alterations were also confirmed in aqueous humor from a novel murine model that spontaneously develops iris atrophy, leading to CEnC loss. The application of the integrative multiomics performed in human samples to the novel murine model will help the development of therapeutic modalities for patients with CEnC loss after corneal transplantation.