Wound Healing Society Annual Meeting
May 2002. Baltimore, Maryland

THE CONDITIONAL KNOCK-OUT OF THE TRANSFORMING GROWTH FACTOR TYPE II RECEPTOR IN FIBROBLASTS RESULTS IN IMPAIRED WOUND HEALING Neil A. Bhowmick1, Anna Chytil1, Cher Carlisle2, Eric Neilson3, Jeffrey M. Davidson2*, Harold L. Moses1. Departments of 1Cancer Biology, 2Pathology, and 3Medicine, Vanderbilt University, and *VA Medical Center, Nashville, TN 37232 neil.bhowmick@mcmail.vanderbilt.edu

The transforming growth factor-beta isoforms (TGF-ß1, TGF-ß2, and TGF-ß3) regulate wound healing through autocrine and paracrine signaling. TGF-ß signaling is initiated by its binding to cell surface receptors that form a heterotetrameric complex of two type I and two type II serine/threonine kinase receptors. Based on our previous TGF-ß studies identifying signaling pathways crucial for epithelial-to-mesenchymal transdifferentiation progression, we developed a mouse model that exhibited a conditional knock-out of the TGF-ß type II receptor (TßRII) in fibroblastic cells. Using a Cre-lox approach, targeted fibroblastic recombination was achieved by crossbreeding transgenic mice having both floxed TßRII alleles with those expressing Cre under the FSP-1 (fibroblast specific protein) promoter. FSP-1 is expressed in the mesenchymal cells of fibroblastic origin beginning at embryonic day 9. Analysis of various tissues of the bigenic mice with the intended knock-out, Tgfbr2fspko, show mesenchymal recombination of the Tgfbr2 gene, including the skin. Keratinocytes are recognized as key regulators of skin remodeling, however their interaction with the underlying dermal fibroblasts during wound healing is less clear. The Tgfbr2fspko mouse model uniquely permits such studies. These animals were tested for excision and linear incision wound healing properties through a 7-10 day period, at which time the mice were sacrificed for histological analysis. The keratinocyte organization and the closure of the excisional wound in Tgfbr2fspko mice were similar to that of wild type C57BL/SV6 mice. However there were diminished numbers of cells in the suprabasal layer in the remodeled excision wound of the conditionally knocked-out mice. Interestingly, tensile strength analysis showed that there was essentially no healing of the incisional wound in Tgfbr2fspko mice seven days after wounding. We investigated the expression and distribution of TGF-ß1, integrin, and extracellular matrix proteins. Our findings suggest TGF-ß signaling is important in stromal remodeling and keratinocyte expression.

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