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First published online 8 April 2008
doi: 10.1242/jcs.021683

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Fibroblast migration is mediated by CD44-dependent TGFβ activation

Pinak S. Acharya^1,2,*, Sonali Majumdar^2,*, Michele Jacob², James Hayden², Paul Mrass², Wolfgang Weninger², Richard K. Assoian³ and Ellen Puré^2,4,

¹ Department of Pulmonary and Critical Care Medicine, The University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
² The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
³ Department of Pharmacology, The University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA
⁴ Ludwig Institute of Cancer Research, 3601 Spruce Street, Philadelphia, PA 19104, USA

Author for correspondence (e-mail: pure{at}wistar.org)

Accepted 4 February 2008

CD44 contributes to inflammation and fibrosis in response to injury. As fibroblast recruitment is critical to wound healing, we compared cytoskeletal architecture and migration of wild-type (CD44WT) and CD44-deficient (CD44KO) fibroblasts. CD44KO fibroblasts exhibited fewer stress fibers and focal adhesion complexes, and their migration was characterized by increased velocity but loss of directionality, compared with CD44WT fibroblasts. Mechanistically, we demonstrate that CD44WT cells generated more active TGFβ than CD44KO cells and that CD44 promotes the activation of TGFβ via an MMP-dependent mechanism. Reconstitution of CD44 expression completely rescued the phenotype of CD44KO cells whereas exposure of CD44KO cells to exogenous active TGFβ rescued the defect in stress fibers and migrational velocity, but was not sufficient to restore directionality of migration. These results resolve the TGFβ-mediated and TGFβ-independent effects of CD44 on fibroblast migration and suggest that CD44 may be critical for the recruitment of fibroblasts to sites of injury and the function of fibroblasts in tissue remodeling and fibrosis.

Key words: CD44, Cytoskeleton, Fibroblast, TGFβ, Migration, Integrin, Matrix metalloproteinase