Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms.
Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) markedly potentiate tissue repair in vivo. In the present experiments, both in vitro and in vivo responses to PDGF and TGF-beta were tested to identify mechanisms whereby these growth factors might each enhance the wound-healing response. Recombinant human PDGF B-chain homodimers (PDGF-BB) and TGF-beta 1 had identical dose-response curves in chemotactic assays with monocytes and fibroblasts as the natural proteins from platelets. Single applications of PDGF-BB (2 micrograms, 80 pmol) and TGF-beta 1 (20 micrograms, 600 pmol) were next applied to linear incisions in rats and each enhanced the strength required to disrupt the wounds at 5 d up to 212% of paired control wounds. Histological analysis of treated wounds demonstrated an in vivo chemotactic response of macrophages and fibroblasts to both PDGF-BB and to TGF-beta 1 but the response to TGF-beta 1 was significantly less than that observed with PDGF-BB. Marked increases of procollagen type I were observed by immunohistochemical staining in fibroblasts in treated wounds during the first week. The augmented breaking strength of TGF-beta 1 was not observed 2 and 3 wk after wounding. However, the positive influence of PDGF-BB on wound breaking strength persisted through the 7 wk of testing. Furthermore, PDGF-BB-treated wounds had persistently increased numbers of fibroblasts and granulation tissue through day 21, whereas the enhanced cellular influx in TGF-beta 1-treated wounds was not detectable beyond day 7. Wound macrophages and fibroblasts from PDGF-BB-treated wounds contained sharply increased levels of immunohistochemically detectable intracellular TGF-beta. Furthermore, PDGF-BB in vitro induced a marked, time-dependent stimulation of TGF-beta mRNA levels in cultured normal rat kidney fibroblasts. The results suggest that TGF-beta transiently attracts fibroblasts into the wound and may stimulate collagen synthesis directly. In contrast, PDGF is a more potent chemoattractant for wound macrophages and fibroblasts and may stimulate these cells to express endogenous growth factors, including TGF-beta, which, in turn, directly stimulate new collagen synthesis and sustained enhancement of wound healing over a more prolonged period of time.
Pierce
G F
GF
Department of Pathology, Jewish Hospital, Washington University Medical Center, St. Louis, Missouri 63110.
Mustoe
T A
TA
Lingelbach
J
J
Masakowski
V R
VR
Griffin
G L
GL
Senior
R M
RM
Deuel
T F
TF
D000818:Animals; D002465:Cell Movement; D002633:Chemotaxis; D003094:Collagen / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology*; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology*; D009000:Monocytes / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011347:Procollagen / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D015291:Transforming Growth Factors / Q000502:physiology*; D014945:Wound Healing
D010982:Platelet-Derived Growth Factor; D011347:Procollagen; D015291:Transforming Growth Factors; D003094:Collagen