Chimera Analysis Reveals That Fibroblasts and Endothelial Cells Require Platelet-Derived Growth Factor Receptor?Expression for Participation in Reactive Connective Tissue Formation in Adults but Not during Development

摘要

The hypothesis that platelet-derived growth factor (PDGF) plays an important role in repair of connective tissue has been difficult to test experimentally, in part because the disruption of any of the PDGF ligand and receptor genes is embryonic lethal. We have developed a method that circumvents the embryonic lethality of the PDGF receptor (R)ß-/- genotype and minimizes the tendency of compensatory processes to mask the phenotype of gene disruption by comparing the behavior of wild-type and PDGFRß-/- cells within individual chimeric mice. This quantitative chimera analysis method has revealed that during development PDGFRß expression is important for all muscle lineages but not for fibroblast or endothelial lineages. Here we report that fibroblasts and endothelial cells, but not leukocytes, are dependent on PDGFRß expression during the formation of new connective tissue in and around sponges implanted under the skin. Even the 50% reduction in PDGFRß gene dosage in PDGFRß+/- cells reduces fibroblast and endothelial cell participation by 85%. These results demonstrate that the PDGFRß/PDGF B-chain system plays an important direct role in driving both fibroblast and endothelial cell participation in connective tissue repair, that cell behavior can be regulated by relatively small changes in PDGFRß expression, and that the functions served by PDGF in wound healing are different from the roles served during development.