June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Keratocyte-specific ablation of Tgfbr1 gene manifests human keratoconus phenotype in mice
Author Affiliations & Notes
  • Yen-Chiao Wang
    Indiana University, Bloomington, Indiana, United States
  • Footnotes
    Commercial Relationships   Yen-Chiao Wang None
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Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2413 – A0216. doi:
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      Yen-Chiao Wang; Keratocyte-specific ablation of Tgfbr1 gene manifests human keratoconus phenotype in mice. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2413 – A0216.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We previously showed that deletion of Transforming Growth Factor beta (TGF-β) signaling pathway via ablation of its type-2 receptor (TbR2) and Smad4 resulted in thin stroma phenotype similar to the human corneal ectasia disease known as keratoglobus. Herein, we tested the role of Tgfbr1 in the same scenario.

Methods : Transforming growth factor-b type 1 receptor (Tgfbr1) was designed to be conditionally knocked out (Tgfbr1kera-cko) from keratocytes. A novel triple transgenic mice: KerartTA;tetO-Cre;TbR1f/f, were administered with doxycycline (Dox) from postnatal day 1 (P1) to various developing stages including postnatal day 21 (P21), P56. Optical coherence tomography (OCT) was performed to examine corneal thickness and radius of curvature. Bulging appearance was measured and compared to the wild-type littermates (WT). We further compare corneal bulging among Tgfbr1Kera-cko, Smad4Kera-cko and Tgfbr2Kera-cko mice.

Results : The OCT scanning appeared a doom-shaped cornea in the WT but an ectasia cornea with hyper-reflectivity of the corneal stroma was observed in Tgfbr1kera-cko. Moreover, overall corneal thickness in Tgfbr1kera-cko becomes ~60% thinner than that of WT at P21. In the hematoxylin and eosin staining, we observed the uneven thinning and missing stroma in Tgfbr1kera-cko. Unlike Tgfbr2Kera-cko or Smad4Kera-cko which revealed 45-50% thinner stroma throughout the entire cornea, more severe phenotypes including the uneven thinning and disappearing stroma were observed in Tgfbr1kera-cko. Moreover, OCT imaging also revealed corneal bulging suggesting ectasia in Tgfbr1kera-cko mice.

Conclusions : The aforementioned corneal phenotypes in this Tgfbr1kera-cko triple transgenic mouse strain resemble keratoconus in human, which suggest that TGF-ß signaling pathway may play an important role in keratoconus pathophysiology and defect of Tgfbr1 may serve as a potential genetic cause of human keratoconus.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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