Mechanism of human dermal fibroblast migration driven by type I collagen and platelet-derived growth factor-BB

• Published in: Molecular biology of the cell Vol. 15; no. 1; pp. 294 - 309
• Main Authors: Li, Wei, Fan, Jianhua, Chen, Mei, Guan, Shengxi, Sawcer, David, Bokoch, Gary M, Woodley, David T
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 01.01.2004
• Subjects: Becaplermin; cdc42 GTP-Binding Protein - metabolism; Cell Movement - physiology; Cells, Cultured; Collagen Type I - metabolism; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Gene Expression Regulation - physiology; Humans; Image Processing, Computer-Assisted; MAP Kinase Signaling System - physiology; Models, Molecular; Platelet-Derived Growth Factor - metabolism; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Signal Transduction - physiology; Skin - metabolism
• ISSN: 1059-1524; 1939-4586; 1059-1524
• DOI: 10.1091/mbc.e03-05-0352

Migration of human dermal fibroblasts (HDFs) is critical for skin wound healing. The mechanism remains unclear. We report here that platelet-derived growth factor-BB (PDGF-BB) is the major promotility factor in human serum for HDF motility on type I collagen. PDGF-BB recapitulates the full promotility activity of human serum and anti-PDGF neutralizing antibodies completely block it. Although collagen matrix initiates HDF migration without growth factors, PDGF-BB-stimulated migration depends upon attachment of the cells to a collagen matrix. The PDGF-BB's role is to provide directionality and further enhancement for the collagen-initiated HDF motility. To study the collagen and PDGF-BB "dual signaling" in primary HDF, we establish "gene cassettes" plus lentiviral gene delivery approach, in which groups of genes are studied individually or in combination for their roles in HDF migration. Focal adhesion kinase, p21(Rac,CDC42)-activated kinase and Akt are grouped into an upstream kinase gene cassette, and the four major mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2, p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase 5) are grouped into a downstream kinase gene cassette. The experiments demonstrate 1) the genes' individual roles and specificities, 2) their combined effects and sufficiency, and 3) the mechanisms of their intermolecular connections in HDF migration driven by collagen and PDGF-BB.