Deletion of the PDGFR-β Gene Affects Key Fibroblast Functions Important for Wound Healing

Abstract

Platelet-derived growth factors (PDGFs) 1 are major mitogens for connective tissue cells that are involved in diverse biological processes including physiological development, tissue repair, tumorigenesis, and atherosclerosis (1). PDGF family members, PDGF-A, -B, -C, and -D, are assembled as disulfide-linked homo-or heterodimers and exert their activity by binding to and activating specific high affinity cell surface receptors. Two receptor subtypes with protein-tyrosine kinase activity have been identified that can form homo-and heterodimeric receptor complexes: the ␣-subunit, which can bind to the A-, B-, and C-chains of PDGF, and the ␤-subunit, specific for the B-, C-and D-chains (1-4). Dermal fibroblasts are one of the major target cells of PDGF in the initiation and propagation of wound healing in the skin (5). Levels of PDGF receptor (PDGFR)-␣ expression are high in fibroblasts during early embryogenesis, and disruption of PDGFR-␣ results in a reduction in fibroblasts throughout the embryo (6, 7). In contrast, targeted deletion of PDGFR-␤ and analysis of blastocyst chimeras demonstrated no effect of PDGFR-␤ on fibroblast development (8, 9). However, in mice prepared from the blastocyst chimeras that contain a combination of wild-type and PDGFR-␤ Ϫ/Ϫ cells, analysis of granulation tissue formation following the subcutaneous implantation of sponges demonstrated that PDGFR-␤ Ϫ/Ϫ cells were depleted in the granulation tissue (10). These reports suggest that the two subtypes of PDGFR play distinct roles in development and that PDGFR-␤ is important in wound healing by dermal fibroblasts. Analysis of mutant mice in which the cytoplasmic signaling domain of the PDGFR-␤ was used to replace the PDGFR-␣ cytoplasmic domain showed no obvious defects in any of the PDGFR-␣-dependent cell types (11). On the other hand, when the PDGFR-␤ was dependent upon PDGFR-␣ cytoplasmic domain, multiple abnormalities occurred in vascular smooth muscle cell development (11). These data suggest that PDGFR-␤ has unique signaling capacities compared with PDGFR-␣.PDGF binding to the receptors activates a variety of intracellular signaling molecules (12). One of these is phosphatidylinositol 3-kinase (PI3K), which results in the local accumulation of PI(3,4,5)P 3 at the plasma membrane. Synthesized * This study was supported in part by Grants-in-aid for Scientific Research 16390114 and 12470053 from the Ministry of Education, Science, and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.§ § To whom correspondence should be addressed: Dept.

Collagen Fibril Flow and Tissue Translocation Coupled to Fibroblast Migration in 3D Collagen Matrices

“…Previously, we showed that PDGF but not LPA or FBS stimulates human fibroblast migration in nested collagen matrices . Serum frequently has been used as an agonist to study cell migration, and PDGF is believed to be the major promigratory factor for fibroblasts in serum (Li et al, 2004;Gao et al, 2005). However, serum also contains the lipid growth factor sphingosine-1-phosphate (Eichholtz et al, 1993;Yatomi et al, 1997).…”

Pericyte–fibroblast transition promotes tumor growth and metastasis

“…To further define the receptor signaling pathways that mediate PDGF-BB-recruited CAFs and CAMFs, we genetically deleted PDGFRβ in mice in a conditional knockout model (29,30). Deletion of PDGFRβ significantly decreased vascular pericyte coverage in PDGF-BBnegative control vector tumors, supporting the vascular function of PDGF-BB in recruitment of pericytes to angiogenic vessels ( Fig.…”

Platelet-Derived Growth Factor-β Receptor Activation Is Essential for Fibroblast and Pericyte Recruitment during Cutaneous Wound Healing

“…3 Cultured dermal fibroblasts lacking functional PDGFR-␤ show impaired mitosis and complete inhibition of migration with decreased phosphorylation of Akt, extracellular signal-regulated kinase (ERK)1/2, and c-Jun NH 2 -terminal protein kinase (JNK), but not p38 mitogenactivated protein kinase (MAPK). 15 The addition of exogenous PDGF-BB increases fibroblast proliferation and migration into the wound, indirectly leading to both increased extracellular matrix production and wound tensile strength. 16,17 In addition, overexpression of PDGFR-␤ within lesional connective tissue compartments has been noted in several fibrotic disorders including systemic sclerosis 18 and dermal scarring.…”