Koc Ali Can, Sari Vedat, Kocak Gamze, Recber Tuba, Nemutlu Emirhan, Aberdam Daniel, Güven Sinan
Izmir Biomedicine and Genome Center, 35340, Izmir, Türkiye.
Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, 35340, Izmir, Türkiye.
BMC Ophthalmol. 2025 Jan 10;25(1):14. doi: 10.1186/s12886-024-03831-w.
Aniridia is a rare panocular disease caused by gene mutation in the PAX6, which is essential for eye development. Aniridia is inherited in an autosomal dominant manner, but its phenotype can vary significantly among individuals with the same mutation. Animal models, such as drosophila, zebrafish, and rodents, have been used to study aniridia through Pax6 deletions. Recently, patient-derived limbal epithelial stem cells (LESCs) and human-induced pluripotent stem cells (hiPSCs) have been used to model the disease in vitro, providing new insights into therapeutic strategies.
In this study, corneal organoids were generated from hiPSCs derived from aniridia patients with three different PAX6 nonsense mutations, allowing for a detailed comparison between diseased and healthy control models. These organoids structurally mimicked the human cornea and were used to investigate histologic and metabolomic differences between healthy and aniridia-derived samples.
Untargeted metabolomic analysis revealed significant metabolic differences between wild-type (WT) and aniridia-associated keratopathy (AAK) hiPSCs. Further metabolomic profiling at different time points demonstrated distinct metabolic shifts, with amino acid metabolism pathways being consistently enriched in AAK organoids.
This study emphasizes the profound impact of AAK mutations on metabolism, particularly in amino acid biosynthesis and energy metabolism pathways.
无虹膜症是一种罕见的全眼疾病，由PAX6基因突变引起，PAX6对眼睛发育至关重要。无虹膜症以常染色体显性方式遗传，但其表型在具有相同突变的个体之间可能有显著差异。动物模型，如果蝇、斑马鱼和啮齿动物，已被用于通过Pax6缺失研究无虹膜症。最近，患者来源的角膜缘上皮干细胞（LESCs）和人诱导多能干细胞（hiPSCs）已被用于在体外模拟该疾病，为治疗策略提供了新的见解。
在本研究中，从患有三种不同PAX6无义突变的无虹膜症患者来源的hiPSCs中生成角膜类器官，以便对患病模型和健康对照模型进行详细比较。这些类器官在结构上模拟了人类角膜，并用于研究健康样本和无虹膜症来源样本之间的组织学和代谢组学差异。
非靶向代谢组学分析揭示了野生型（WT）和无虹膜症相关角膜病变（AAK）hiPSCs之间存在显著的代谢差异。在不同时间点进行的进一步代谢组学分析显示出明显的代谢变化，氨基酸代谢途径在AAK类器官中持续富集。
本研究强调了AAK突变对代谢的深远影响，特别是在氨基酸生物合成和能量代谢途径方面。
