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Journal of Biochemistry Advance Access published online on September 6, 2008
Journal of Biochemistry, doi:10.1093/jb/mvn106
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© 2008 The Japanese Biochemical Society

Genetic modulation of CD44 expression by intragraft fibroblasts

Gordon D Wu1, Hong Wang1, Hui Zhu1, Yao He1, Mark L. Barr2 and Andrew S. Klein1

1Comprehensive Transplant Center, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
2Department of Cardiothoracic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Corresponding author: Dr. Gordon D. Wu, Comprehensive Transplant Center, Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048. Phone: (310) 423-5393. Fax: (310) 423-0565. E-mail: gordon.wu{at}cshs.org

Received March 11, 2008; Accepted August 11, 2008


  Abstract

This study investigated the genetic composition and the functional implication of CD44 species expressed by intragraft fibroblasts. An LEW-to-F344 heart transplant model of chronic rejection was used. Intragraft fibroblasts recovered from the chronically rejecting allografts displayed a 4.5-fold increase in expression of CD44 mRNA when compared with that of the fibroblasts isolated from non-rejecting heart allografts (p<0.01). The intragraft fibroblasts preferentially expressed CD44 variant isoforms containing v1 exon transcript. Automate nucleotide sequence analysis revealed that the majority (90.12%) of the CD44 v1 isoforms expressed by the rejecting graft fibroblasts were encoded by a mutated CD44 mRNA, which contained 2 point mutations and a codon deletion in the v1 coding region. Histochemistry demonstrated a massive deposition of extracellular HA in the rejecting heart allografts. HA was able to promote in vitro fibroblast adhesion, migration in a CD44 dependent manner, and survival in a serum-free culture condition. The study concludes that up-regulation of CD44 v1 isoforms expressed by the intragraft fibroblasts is associated with an increase in the deposition of extracellular HA, the principal ligand for CD44, in the allografts, suggesting that CD44-HA interaction plays an important role in regulating fibroblast recruitment and growth in allografts developing chronic rejection.

Key Words: CD44, HA, intragraft fibroblast, Gene expression, Rat


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