The TCF4 Gene Regulates Apoptosis of Corneal Endothelial Cells in Fuchs Endothelial Corneal Dystrophy

Nakagawa T, Honda T, Yuasa T, Nishiuchi G, Sato M, Tokunaga A, Nakahara M, Tourtas T, Schlötzer-Schrehardt U, Kruse F, Padmanabhan P, Chatterjee A, Sathe G, Ghose V, Janakiraman N, Blake DJ, Koizumi N, Elchuri S, Okumura N (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Investigative Ophthalmology & Visual Science Association for Research in Vision and Ophthalmology (ARVO)

Book Volume: 66

Article Number: 16

Journal Issue: 3

DOI: 10.1167/iovs.66.3.16

Abstract

PURPOSE. Fuchs endothelial corneal dystrophy (FECD) is a progressive corneal disorder characterized by excessive extracellular matrix (ECM) accumulation and corneal endothelial cell death. CTG trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene represents the most significant genetic risk factor. This study aimed to elucidate the role of TCF4 in FECD pathogenesis through comprehensive proteomic analysis. METHODS. Corneal endothelial cells isolated from patients with FECD harboring TCF4 trinucleotide repeat expansion were immortalized to establish an FECD cell model (iFECD). CRISPR/Cas9-mediated genome editing was employed to generate TCF4-knockout iFECD cells. Whole-cell proteome analysis was performed using liquid chromatography–mass spectrometry, followed by pathway enrichment analysis of differentially expressed proteins (DEPs). The effects of TCF4 deletion on TGF-β–mediated protein aggregation and cell death were evaluated using Western blot analysis, flow cytometry, and aggresome detection assays. RESULTS. Proteomic analysis identified 88 DEPs among 6510 detected proteins. Pathway analysis revealed significant enrichment in ECM-associated pathways, oxidative stress responses, and cellular motility. TCF4 deletion attenuated TGF-β–induced cell death in iFECD cells. Concordantly, Western blot analysis demonstrated that TCF4 deletion suppressed TGF-β2–mediated cleavage of caspase-3 and poly (ADP-ribose) polymerase. Flow cytometric analysis of Annexin V–positive cells confirmed reduced apoptosis in TCF4-deleted cells following TGF-β2 treatment. Additionally, aggresome detection assays revealed that TCF4 deletion diminished TGF-β2–induced protein aggregation. CONCLUSIONS. This study demonstrates a crucial role for TCF4 in FECD pathogenesis, particularly in ECM regulation and protein aggregation–induced cell death.

Authors with CRIS profile

Theofilos Tourtas Lehrstuhl für Augenheilkunde Ursula Schlötzer-Schrehardt Medizinische Fakultät Friedrich Kruse Lehrstuhl für Augenheilkunde

Involved external institutions

Doshisha University / 同志社大学 JP Japan (JP) Sankara Nethralaya IN India (IN) Cardiff University GB United Kingdom (GB)

How to cite

APA:

Nakagawa, T., Honda, T., Yuasa, T., Nishiuchi, G., Sato, M., Tokunaga, A.,... Okumura, N. (2025). The TCF4 Gene Regulates Apoptosis of Corneal Endothelial Cells in Fuchs Endothelial Corneal Dystrophy. Investigative Ophthalmology & Visual Science, 66(3). https://doi.org/10.1167/iovs.66.3.16

MLA:

Nakagawa, Tatsuya, et al. "The TCF4 Gene Regulates Apoptosis of Corneal Endothelial Cells in Fuchs Endothelial Corneal Dystrophy." Investigative Ophthalmology & Visual Science 66.3 (2025).

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