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J Cell Biol. Jul 1, 1989; 109(1): 429–440.
PMCID: PMC2115493

Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Assoian RK, Sporn MB. Type beta transforming growth factor in human platelets: release during platelet degranulation and action on vascular smooth muscle cells. J Cell Biol. 1986 Apr;102(4):1217–1223. [PMC free article] [PubMed]
  • Barrett TB, Benditt EP. Platelet-derived growth factor gene expression in human atherosclerotic plaques and normal artery wall. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2810–2814. [PMC free article] [PubMed]
  • Bassols A, Massagué J. Transforming growth factor beta regulates the expression and structure of extracellular matrix chondroitin/dermatan sulfate proteoglycans. J Biol Chem. 1988 Feb 25;263(6):3039–3045. [PubMed]
  • Bauer EA, Cooper TW, Huang JS, Altman J, Deuel TF. Stimulation of in vitro human skin collagenase expression by platelet-derived growth factor. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4132–4136. [PMC free article] [PubMed]
  • Blatti SP, Foster DN, Ranganathan G, Moses HL, Getz MJ. Induction of fibronectin gene transcription and mRNA is a primary response to growth-factor stimulation of AKR-2B cells. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1119–1123. [PMC free article] [PubMed]
  • Chen JK, Hoshi H, McKeehan WL. Transforming growth factor type beta specifically stimulates synthesis of proteoglycan in human adult arterial smooth muscle cells. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5287–5291. [PMC free article] [PubMed]
  • Cheng SL, Rifas L, Shen V, Tong B, Pierce G, Deuel T, Peck WA. J774A.1 macrophage cell line produces PDGF-like and non-PDGF-like growth factors for bone cells. J Bone Miner Res. 1987 Oct;2(5):467–474. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Chua CC, Geiman DE, Keller GH, Ladda RL. Induction of collagenase secretion in human fibroblast cultures by growth promoting factors. J Biol Chem. 1985 May 10;260(9):5213–5216. [PubMed]
  • Collins T, Pober JS, Gimbrone MA, Jr, Hammacher A, Betsholtz C, Westermark B, Heldin CH. Cultured human endothelial cells express platelet-derived growth factor A chain. Am J Pathol. 1987 Jan;126(1):7–12. [PMC free article] [PubMed]
  • Davidson JM, Klagsbrun M, Hill KE, Buckley A, Sullivan R, Brewer PS, Woodward SC. Accelerated wound repair, cell proliferation, and collagen accumulation are produced by a cartilage-derived growth factor. J Cell Biol. 1985 Apr;100(4):1219–1227. [PMC free article] [PubMed]
  • Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985 Aug 22;316(6030):701–705. [PubMed]
  • Deuel TF. Polypeptide growth factors: roles in normal and abnormal cell growth. Annu Rev Cell Biol. 1987;3:443–492. [PubMed]
  • Deuel TF, Senior RM. Growth factors in fibrotic diseases. N Engl J Med. 1987 Jul 23;317(4):236–237. [PubMed]
  • Deuel TF, Senior RM, Huang JS, Griffin GL. Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J Clin Invest. 1982 Apr;69(4):1046–1049. [PMC free article] [PubMed]
  • Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Docherty AJ, Angel P, Heath JK. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J. 1987 Jul;6(7):1899–1904. [PMC free article] [PubMed]
  • Ellingsworth LR, Brennan JE, Fok K, Rosen DM, Bentz H, Piez KA, Seyedin SM. Antibodies to the N-terminal portion of cartilage-inducing factor A and transforming growth factor beta. Immunohistochemical localization and association with differentiating cells. J Biol Chem. 1986 Sep 15;261(26):12362–12367. [PubMed]
  • Grotendorst GR, Martin GR, Pencev D, Sodek J, Harvey AK. Stimulation of granulation tissue formation by platelet-derived growth factor in normal and diabetic rats. J Clin Invest. 1985 Dec;76(6):2323–2329. [PMC free article] [PubMed]
  • Hunt TK, Knighton DR, Thakral KK, Goodson WH, 3rd, Andrews WS. Studies on inflammation and wound healing: angiogenesis and collagen synthesis stimulated in vivo by resident and activated wound macrophages. Surgery. 1984 Jul;96(1):48–54. [PubMed]
  • Ignotz RA, Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed]
  • Ignotz RA, Endo T, Massagué J. Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-beta. J Biol Chem. 1987 May 15;262(14):6443–6446. [PubMed]
  • Jaye M, McConathy E, Drohan W, Tong B, Deuel T, Maciag T. Modulation of the sis gene transcript during endothelial cell differentiation in vitro. Science. 1985 May 17;228(4701):882–885. [PubMed]
  • Keski-Oja J, Raghow R, Sawdey M, Loskutoff DJ, Postlethwaite AE, Kang AH, Moses HL. Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-beta. Divergent responses in lung fibroblasts and carcinoma cells. J Biol Chem. 1988 Mar 5;263(7):3111–3115. [PubMed]
  • Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975 Jan;78(1):71–100. [PMC free article] [PubMed]
  • Leof EB, Proper JA, Goustin AS, Shipley GD, DiCorleto PE, Moses HL. Induction of c-sis mRNA and activity similar to platelet-derived growth factor by transforming growth factor beta: a proposed model for indirect mitogenesis involving autocrine activity. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2453–2457. [PMC free article] [PubMed]
  • LEVENSON SM, GEEVER EF, CROWLEY LV, OATES JF, 3rd, BERARD CW, ROSEN H. THE HEALING OF RAT SKIN WOUNDS. Ann Surg. 1965 Feb;161:293–308. [PMC free article] [PubMed]
  • Lund LR, Riccio A, Andreasen PA, Nielsen LS, Kristensen P, Laiho M, Saksela O, Blasi F, Danø K. Transforming growth factor-beta is a strong and fast acting positive regulator of the level of type-1 plasminogen activator inhibitor mRNA in WI-38 human lung fibroblasts. EMBO J. 1987 May;6(5):1281–1286. [PMC free article] [PubMed]
  • Madden JW, Peacock EE., Jr Studies on the biology of collagen during wound healing. I. Rate of collagen synthesis and deposition in cutaneous wounds of the rat. Surgery. 1968 Jul;64(1):288–294. [PubMed]
  • Majesky MW, Benditt EP, Schwartz SM. Expression and developmental control of platelet-derived growth factor A-chain and B-chain/Sis genes in rat aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1524–1528. [PMC free article] [PubMed]
  • Martinet Y, Bitterman PB, Mornex JF, Grotendorst GR, Martin GR, Crystal RG. Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity. Nature. 1986 Jan 9;319(6049):158–160. [PubMed]
  • Martinet Y, Rom WN, Grotendorst GR, Martin GR, Crystal RG. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med. 1987 Jul 23;317(4):202–209. [PubMed]
  • Mecham RP, Lange G, Madaras J, Starcher B. Elastin synthesis by ligamentum nuchae fibroblasts: effects of culture conditions and extracellular matrix on elastin production. J Cell Biol. 1981 Aug;90(2):332–338. [PMC free article] [PubMed]
  • Milbrandt J. A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science. 1987 Nov 6;238(4828):797–799. [PubMed]
  • Mustoe TA, Pierce GF, Thomason A, Gramates P, Sporn MB, Deuel TF. Accelerated healing of incisional wounds in rats induced by transforming growth factor-beta. Science. 1987 Sep 11;237(4820):1333–1336. [PubMed]
  • Nathan CF. Secretory products of macrophages. J Clin Invest. 1987 Feb;79(2):319–326. [PMC free article] [PubMed]
  • Paulsson Y, Hammacher A, Heldin CH, Westermark B. Possible positive autocrine feedback in the prereplicative phase of human fibroblasts. Nature. 1987 Aug 20;328(6132):715–717. [PubMed]
  • Penttinen RP, Kobayashi S, Bornstein P. Transforming growth factor beta increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1105–1108. [PMC free article] [PubMed]
  • Pierce GF, Mustoe TA, Lingelbach J, Masakowski VR, Gramates P, Deuel TF. Transforming growth factor beta reverses the glucocorticoid-induced wound-healing deficit in rats: possible regulation in macrophages by platelet-derived growth factor. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2229–2233. [PMC free article] [PubMed]
  • Pierce GF, Mustoe TA, Senior RM, Reed J, Griffin GL, Thomason A, Deuel TF. In vivo incisional wound healing augmented by platelet-derived growth factor and recombinant c-sis gene homodimeric proteins. J Exp Med. 1988 Mar 1;167(3):974–987. [PMC free article] [PubMed]
  • Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med. 1987 Jan 1;165(1):251–256. [PMC free article] [PubMed]
  • Raghow R, Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Transforming growth factor-beta increases steady state levels of type I procollagen and fibronectin messenger RNAs posttranscriptionally in cultured human dermal fibroblasts. J Clin Invest. 1987 Apr;79(4):1285–1288. [PMC free article] [PubMed]
  • Rappolee DA, Mark D, Banda MJ, Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science. 1988 Aug 5;241(4866):708–712. [PubMed]
  • Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4167–4171. [PMC free article] [PubMed]
  • Roberts CJ, Birkenmeier TM, McQuillan JJ, Akiyama SK, Yamada SS, Chen WT, Yamada KM, McDonald JA. Transforming growth factor beta stimulates the expression of fibronectin and of both subunits of the human fibronectin receptor by cultured human lung fibroblasts. J Biol Chem. 1988 Apr 5;263(10):4586–4592. [PubMed]
  • Ross R. The fibroblast and wound repair. Biol Rev Camb Philos Soc. 1968 Feb;43(1):51–96. [PubMed]
  • Rossi P, Karsenty G, Roberts AB, Roche NS, Sporn MB, de Crombrugghe B. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-beta. Cell. 1988 Feb 12;52(3):405–414. [PubMed]
  • Senior RM, Griffin GL, Huang JS, Walz DA, Deuel TF. Chemotactic activity of platelet alpha granule proteins for fibroblasts. J Cell Biol. 1983 Feb;96(2):382–385. [PMC free article] [PubMed]
  • Seppä H, Grotendorst G, Seppä S, Schiffmann E, Martin GR. Platelet-derived growth factor in chemotactic for fibroblasts. J Cell Biol. 1982 Feb;92(2):584–588. [PMC free article] [PubMed]
  • Shalaby MR, Ammann AJ. Suppression of immune cell function in vitro by recombinant human transforming growth factor-beta. Cell Immunol. 1988 Apr 1;112(2):343–350. [PubMed]
  • Shimokado K, Raines EW, Madtes DK, Barrett TB, Benditt EP, Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985 Nov;43(1):277–286. [PubMed]
  • Sporn MB, Roberts AB, Shull JH, Smith JM, Ward JM, Sodek J. Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science. 1983 Mar 18;219(4590):1329–1331. [PubMed]
  • Sporn MB, Roberts AB, Wakefield LM, de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987 Sep;105(3):1039–1045. [PMC free article] [PubMed]
  • Sprugel KH, McPherson JM, Clowes AW, Ross R. Effects of growth factors in vivo. I. Cell ingrowth into porous subcutaneous chambers. Am J Pathol. 1987 Dec;129(3):601–613. [PMC free article] [PubMed]
  • Tzeng DY, Deuel TF, Huang JS, Senior RM, Boxer LA, Baehner RL. Platelet-derived growth factor promotes polymorphonuclear leukocyte activation. Blood. 1984 Nov;64(5):1123–1128. [PubMed]
  • Tzeng DY, Deuel TF, Huang JS, Baehner RL. Platelet-derived growth factor promotes human peripheral monocyte activation. Blood. 1985 Jul;66(1):179–183. [PubMed]
  • Van Obberghen-Schilling E, Roche NS, Flanders KC, Sporn MB, Roberts AB. Transforming growth factor beta 1 positively regulates its own expression in normal and transformed cells. J Biol Chem. 1988 Jun 5;263(16):7741–7746. [PubMed]
  • Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5788–5792. [PMC free article] [PubMed]

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