Establishment of a Disease Model Using Patient-Specific Induced Pluripotent Stem Cells-Derived Trabecular Meshwork Cells in a Chinese Primary Open-Angle Glaucoma Mega-Pedigree

BACKGROUND:Primary open-angle glaucoma (POAG) is one of the most common insidious blinding eye diseases. Understanding the pathogenic mechanisms of it is extremely important. It is accepted that POAG attacks specific ocular tissue, such as trabecular meshwork and optic nerve damage, which causes elevated intraocular pressure and optic nerve damage. This study aimed to develop a preliminary prediction model for this disease by establishing the patient-specific induced pluripotent stem cells (iPSCs)-derived trabecular meshwork cells (TMCs) (p-iPSCs-TMCs) in the largest POAG family named "GZ.1" in China and preliminarily analyze the pathogenic mechanisms. METHODS:Peripheral blood of patients in GZ.1 and healthy individuals not belonging to the family were collected and reprogrammed into iPSCs. Then, the iPSCs were differentiated into iPSCs-TMCs. Next, their morphology and function were compared. Finally, their pathogenic mechanisms were analyzed. RESULTS:The patient-specific iPSCs (p-iPSCs) and healthy individual-specific iPSCs (n-iPSCs) were all successfully generated. Their morphology was quite similar to each other. However, p-iPSCs-TMCs exhibited compromised morphology and function. p-iPSCs-TMCs displayed the morphology of heterogeneous distribution and accumulation in clusters, while n-iPSCs-derived TMCs (n-iPSCs-TMCs) showed a uniformly distributed and homogenous appearance. Moreover, p-iPSCs-TMCs showed greater cell apoptosis (p < 0.01), impaired proliferating ability (24-h and 48-h time points: p < 0.05, 72-h and 96-h time points: p < 0.001), production of reactive oxygen species (p < 0.05), and impaired phagocytosis ability than n-iPSCs-TMCs (24-h, 48-h, and 72-h time points: p < 0.0001, 96-h time point: p < 0.001). CONCLUSION:The p-iPSCs-TMCs can be successfully differentiated from peripheral blood, while the cells show impaired morphology and function compared with n-iPSCs-TMCs. Given this, p-iPSCs-TMCs can serve as an ideal disease model for POAG in GZ.1. Our study on the morphology and function of iPSCs-TMCs in GZ.1 may provide a valuable tool for elucidating the pathogenesis of POAG.