Genome-Wide Transcriptional Analysis of Differentially Expressed Genes in Diabetic, Healing Corneal Epithelial Cells: Hyperglycemia-Suppressed TGFβ3 Expression Contributes to the Delay of Epithelial Wound Healing in Diabetic Corneas

  1. Fu-Shin X. Yu1
  1. 1Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI
  2. 2Genomic Core Laboratory of National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
  3. 3Xiamen Eye Center, Key Laboratory of Ophthalmology and Visual Science of Fujian Province, Xiamen University, Xiamen, Fujian, China
  1. Corresponding author: Fu-Shin X. Yu, fyu{at}med.wayne.edu.
  1. I.B., H.S., and N.G. contributed equally to this work.

Abstract

Patients with diabetes mellitus (DM) may develop corneal complications and delayed wound healing. The aims of this study are to characterize the molecular signatures and biological pathways leading to delayed epithelial wound healing and to delineate the involvement of TGFβ3 therein. Genome-wide cDNA microarray analysis revealed 1,888 differentially expressed genes in the healing epithelia of normal (NL) versus type 1 DM rat corneas. Gene ontology and enrichment analyses indicated TGFβ signaling as a major altered pathway. Among three TGFβ isoforms, TGF-β1 and β3 were upregulated in response to wounding in NL corneal epithelial cells (CECs), whereas the latter was greatly suppressed by hyperglycemia in rat type 1 and 2 and mouse type 1 DM models. Functional analysis indicated that TGF-β3 contributed to wound healing in NL corneas. Moreover, exogenously added TGF-β3 accelerated epithelial wound closure in type 2 rat and type 1 mouse DM corneas via Smad and PI3K-AKT signaling pathways, autoregulation, and/or upregulation of Serpine1, a well-known TGFβ target gene. Taken together, our study for the first time provides a comprehensive list of genes differentially expressed in the healing CECs of NL versus diabetic corneas and suggests the therapeutic potential of TGF-β3 for treating corneal and skin wounds in diabetic patients.

Footnotes

  • Received August 15, 2013.
  • Accepted October 25, 2013.

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  1. Diabetes vol. 63 no. 2 715-727
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