Mechanism of human dermal fibroblast migration driven by type I collagen and platelet-derived growth factor-BB.
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.
Li
Wei
W
The Division of Dermatology and the University of Southern California/Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA. wli@hsc.usc.edu
Fan
Jianhua
J
Chen
Mei
M
Guan
Shengxi
S
Sawcer
David
D
Bokoch
Gary M
GM
Woodley
David T
DT
D000077214:Becaplermin; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D020935:MAP Kinase Signaling System / Q000502:physiology; D008958:Models, Molecular; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D024042:Collagen Type I; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020764:cdc42 GTP-Binding Protein