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(Investigative Ophthalmology and Visual Science. 2003;44:1850-1858.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.02-0973
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Myofibroblast Differentiation of Normal Human Keratocytes and hTERT, Extended-Life Human Corneal Fibroblasts

James V. Jester,1 Jiying Huang,1 Stephen Fisher,1 Jennifer Spiekerman,1 Jin Ho Chang,1 Woodring E. Wright,2 and Jerry W. Shay2

1From the Departments of Ophthalmology and 2Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.

PURPOSE. The purpose of this study was to determine whether TGFß induces myofibroblast differentiation in cultured human keratocytes and in telomerase (hTERT)-immortalized human corneal fibroblast cell lines.

METHODS. Normal human corneal keratocytes were isolated from donor corneas of various ages and grown under serum-free (cultured keratocytes) or serum-added (corneal fibroblasts) conditions. Corneal fibroblasts were infected with the MPSV-hTERT retroviral vector, and selected clones were isolated and characterized by chromosomal karyotyping. The responses of normal cultured keratocytes and serum-starved corneal fibroblasts to TGFß in the presence or absence of Arg-Gly-Asp (RGD)-containing peptides and neutralizing antibodies to platelet-derived growth factor (PDGF) were characterized by immunocytochemistry, Western blot analysis, and real-time PCR, to identify assembly of actin filaments, formation of focal adhesions, and expression of {alpha}-smooth muscle actin ({alpha}-SMA).

RESULTS. Treatment of cultured keratocytes with TGFß (1 ng/mL) induced cell spreading, assembly of actin filaments, formation of focal adhesions, and expression of {alpha}-SMA, which was blocked by the addition of RGD-containing peptides (100 µM). A similar response was identified in hTERT-expressing human corneal fibroblast cell lines, showing a 69-fold increase in {alpha}-SMA message. Furthermore, treatment of hTERT corneal fibroblasts with RGD or anti-PDGF inhibited myofibroblast differentiation. Karyotype analysis of hTERT corneal fibroblasts identified age-dependent chromosomal aberrations in cells of older donors but not in those of a 10-year-old donor.

CONCLUSIONS. Induction of myofibroblast differentiation by TGFß in cultured human keratocytes and hTERT corneal fibroblasts occurs through a similar signal transduction pathway to that previously identified in the rabbit, which involves an autocrine PDGF feedback loop.




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