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. 1993 May;91(5):2065–2075. doi: 10.1172/JCI116429

Tissue localization of beta receptors for platelet-derived growth factor and platelet-derived growth factor B chain during wound repair in humans.

C Reuterdahl 1, C Sundberg 1, K Rubin 1, K Funa 1, B Gerdin 1
PMCID: PMC288205  PMID: 8486774

Abstract

The expression and localization of PDGF beta receptors and PDGF-AB/BB in human healing wounds was evaluated by immunohistochemical techniques and in situ hybridization. Expression of PDGF beta receptor protein and PDGF-AB/BB were analyzed in wound margin biopsies using the PDGFR-B2 and PDGF 007 antibodies. PDGF beta receptor expression was minor in normal skin. An increased expression of PDGF beta receptor protein was prominent in vessels in the proliferating tissue zone in wounds as early as 1 d after surgery and was apparent < or = 4 wk after surgery. There was also a concordant increase in PDGF beta receptor mRNA detected by in situ hybridization. PDGF-AB/BB was present in healing wounds as well as in normal skin. In normal skin, expression of PDGF-AB/BB was confined to peripheral nerve fibers and to solitary cells of the epidermis and of the superficial dermis. In wounds, infiltrating mononuclear cells also stained for PDGF-AB/BB. To identify cell types expressing PDGF AB/BB and PDGF beta receptors, respectively, we performed double immunofluorescence stainings. PDGF beta receptors were expressed by vascular smooth muscle cells and cells in capillary walls; the receptor protein could not be detected in neurofilament containing structures, T lymphocytes, or CD68 expressing macrophages. PDGF-AB/BB colocalized with neurofilaments, it was present in Langerhans cells of the epidermis and in HLA-DR positive cells located in the epidermal/dermal junction area. Of the macrophages infiltrating the wound, 43 +/- 18% stained positively for PDGF AB/BB. Since PDGF-AB/BB and PDGF beta receptors are expressed in the healing wound, two essential prerequisites for a role of PDGF in wound healing are fulfilled.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antoniades H. N., Galanopoulos T., Neville-Golden J., Kiritsy C. P., Lynch S. E. Injury induces in vivo expression of platelet-derived growth factor (PDGF) and PDGF receptor mRNAs in skin epithelial cells and PDGF mRNA in connective tissue fibroblasts. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):565–569. doi: 10.1073/pnas.88.2.565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bar R. S., Boes M., Booth B. A., Dake B. L., Henley S., Hart M. N. The effects of platelet-derived growth factor in cultured microvessel endothelial cells. Endocrinology. 1989 Apr;124(4):1841–1848. doi: 10.1210/endo-124-4-1841. [DOI] [PubMed] [Google Scholar]
  3. Claesson-Welsh L., Eriksson A., Morén A., Severinsson L., Ek B., Ostman A., Betsholtz C., Heldin C. H. cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules. Mol Cell Biol. 1988 Aug;8(8):3476–3486. doi: 10.1128/mcb.8.8.3476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clark R. A., Folkvord J. M., Hart C. E., Murray M. J., McPherson J. M. Platelet isoforms of platelet-derived growth factor stimulate fibroblasts to contract collagen matrices. J Clin Invest. 1989 Sep;84(3):1036–1040. doi: 10.1172/JCI114227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clark R. A. Wound repair. Curr Opin Cell Biol. 1989 Oct;1(5):1000–1008. doi: 10.1016/0955-0674(89)90072-0. [DOI] [PubMed] [Google Scholar]
  6. Cromack D. T., Porras-Reyes B., Mustoe T. A. Current concepts in wound healing: growth factor and macrophage interaction. J Trauma. 1990 Dec;30(12 Suppl):S129–S133. doi: 10.1097/00005373-199012001-00026. [DOI] [PubMed] [Google Scholar]
  7. Eccleston P. A., Collarini E. J., Jessen K. R., Mirsky R., Richardson W. D. Schwann Cells Secrete a PDGF-like Factor: Evidence for an Autocrine Growth Mechanism involving PDGF. Eur J Neurosci. 1990 Oct;2(11):985–992. doi: 10.1111/j.1460-9568.1990.tb00011.x. [DOI] [PubMed] [Google Scholar]
  8. Eckersley J. R., Dudley H. A. Wounds and wound healing. Br Med Bull. 1988 Apr;44(2):423–436. doi: 10.1093/oxfordjournals.bmb.a072259. [DOI] [PubMed] [Google Scholar]
  9. Eriksson A., Siegbahn A., Westermark B., Heldin C. H., Claesson-Welsh L. PDGF alpha- and beta-receptors activate unique and common signal transduction pathways. EMBO J. 1992 Feb;11(2):543–550. doi: 10.1002/j.1460-2075.1992.tb05085.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fellström B., Klareskog L., Heldin C. H., Larsson E., Rönnstrand L., Terracio L., Tufveson G., Wahlberg J., Rubin K. Platelet-derived growth factor receptors in the kidney--upregulated expression in inflammation. Kidney Int. 1989 Dec;36(6):1099–1102. doi: 10.1038/ki.1989.306. [DOI] [PubMed] [Google Scholar]
  11. Funa K., Papanicolaou V., Juhlin C., Rastad J., Akerström G., Heldin C. H., Oberg K. Expression of platelet-derived growth factor beta-receptors on stromal tissue cells in human carcinoid tumors. Cancer Res. 1990 Feb 1;50(3):748–753. [PubMed] [Google Scholar]
  12. Funa K., Steinholtz L., Nou E., Bergh J. Increased expression of N-myc in human small cell lung cancer biopsies predicts lack of response to chemotherapy and poor prognosis. Am J Clin Pathol. 1987 Aug;88(2):216–220. doi: 10.1093/ajcp/88.2.216. [DOI] [PubMed] [Google Scholar]
  13. Gay S., Jones R. E., Jr, Huang G. Q., Gay R. E. Immunohistologic demonstration of platelet-derived growth factor (PDGF) and sis-oncogene expression in scleroderma. J Invest Dermatol. 1989 Feb;92(2):301–303. doi: 10.1111/1523-1747.ep12276895. [DOI] [PubMed] [Google Scholar]
  14. Gullberg D., Tingström A., Thuresson A. C., Olsson L., Terracio L., Borg T. K., Rubin K. Beta 1 integrin-mediated collagen gel contraction is stimulated by PDGF. Exp Cell Res. 1990 Feb;186(2):264–272. doi: 10.1016/0014-4827(90)90305-t. [DOI] [PubMed] [Google Scholar]
  15. Hart C. E., Forstrom J. W., Kelly J. D., Seifert R. A., Smith R. A., Ross R., Murray M. J., Bowen-Pope D. F. Two classes of PDGF receptor recognize different isoforms of PDGF. Science. 1988 Jun 10;240(4858):1529–1531. doi: 10.1126/science.2836952. [DOI] [PubMed] [Google Scholar]
  16. Heldin C. H., Bäckström G., Ostman A., Hammacher A., Rönnstrand L., Rubin K., Nistér M., Westermark B. Binding of different dimeric forms of PDGF to human fibroblasts: evidence for two separate receptor types. EMBO J. 1988 May;7(5):1387–1393. doi: 10.1002/j.1460-2075.1988.tb02955.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heldin C. H., Westermark B. Platelet-derived growth factor: mechanism of action and possible in vivo function. Cell Regul. 1990 Jul;1(8):555–566. doi: 10.1091/mbc.1.8.555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Holthöfer H., Virtanen I., Kariniemi A. L., Hormia M., Linder E., Miettinen A. Ulex europaeus I lectin as a marker for vascular endothelium in human tissues. Lab Invest. 1982 Jul;47(1):60–66. [PubMed] [Google Scholar]
  19. Juhlin C., Holmdahl R., Johansson H., Rastad J., Akerström G., Klareskog L. Monoclonal antibodies with exclusive reactivity against parathyroid cells and tubule cells of the kidney. Proc Natl Acad Sci U S A. 1987 May;84(9):2990–2994. doi: 10.1073/pnas.84.9.2990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kumkumian G. K., Lafyatis R., Remmers E. F., Case J. P., Kim S. J., Wilder R. L. Platelet-derived growth factor and IL-1 interactions in rheumatoid arthritis. Regulation of synoviocyte proliferation, prostaglandin production, and collagenase transcription. J Immunol. 1989 Aug 1;143(3):833–837. [PubMed] [Google Scholar]
  21. Larsen C. P., Steinman R. M., Witmer-Pack M., Hankins D. F., Morris P. J., Austyn J. M. Migration and maturation of Langerhans cells in skin transplants and explants. J Exp Med. 1990 Nov 1;172(5):1483–1493. doi: 10.1084/jem.172.5.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lynch S. E., Nixon J. C., Colvin R. B., Antoniades H. N. Role of platelet-derived growth factor in wound healing: synergistic effects with other growth factors. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7696–7700. doi: 10.1073/pnas.84.21.7696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Orlidge A., D'Amore P. A. Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. J Cell Biol. 1987 Sep;105(3):1455–1462. doi: 10.1083/jcb.105.3.1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pierce G. F., Mustoe T. A., Senior R. M., Reed J., Griffin G. L., Thomason A., Deuel T. F. 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. doi: 10.1084/jem.167.3.974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pierce G. F., Tarpley J. E., Yanagihara D., Mustoe T. A., Fox G. M., Thomason A. Platelet-derived growth factor (BB homodimer), transforming growth factor-beta 1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair. Am J Pathol. 1992 Jun;140(6):1375–1388. [PMC free article] [PubMed] [Google Scholar]
  26. Poulter L. W., Campbell D. A., Munro C., Janossy G. Discrimination of human macrophages and dendritic cells by means of monoclonal antibodies. Scand J Immunol. 1986 Sep;24(3):351–357. doi: 10.1111/j.1365-3083.1986.tb02104.x. [DOI] [PubMed] [Google Scholar]
  27. Remmers E. F., Sano H., Lafyatis R., Case J. P., Kumkumian G. K., Hla T., Maciag T., Wilder R. L. Production of platelet derived growth factor B chain (PDGF-B/c-sis) mRNA and immunoreactive PDGF B-like polypeptide by rheumatoid synovium: coexpression with heparin binding acidic fibroblast growth factor-1. J Rheumatol. 1991 Jan;18(1):7–13. [PubMed] [Google Scholar]
  28. Robson M. C., Phillips L. G., Thomason A., Robson L. E., Pierce G. F. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet. 1992 Jan 4;339(8784):23–25. doi: 10.1016/0140-6736(92)90143-q. [DOI] [PubMed] [Google Scholar]
  29. Ross R., Masuda J., Raines E. W., Gown A. M., Katsuda S., Sasahara M., Malden L. T., Masuko H., Sato H. Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science. 1990 May 25;248(4958):1009–1012. doi: 10.1126/science.2343305. [DOI] [PubMed] [Google Scholar]
  30. Ross R., Raines E. W., Bowen-Pope D. F. The biology of platelet-derived growth factor. Cell. 1986 Jul 18;46(2):155–169. doi: 10.1016/0092-8674(86)90733-6. [DOI] [PubMed] [Google Scholar]
  31. Rubin K., Terracio L., Rönnstrand L., Heldin C. H., Klareskog L. Expression of platelet-derived growth factor receptors is induced on connective tissue cells during chronic synovial inflammation. Scand J Immunol. 1988 Mar;27(3):285–294. doi: 10.1111/j.1365-3083.1988.tb02349.x. [DOI] [PubMed] [Google Scholar]
  32. Rubin K., Tingström A., Hansson G. K., Larsson E., Rönnstrand L., Klareskog L., Claesson-Welsh L., Heldin C. H., Fellström B., Terracio L. Induction of B-type receptors for platelet-derived growth factor in vascular inflammation: possible implications for development of vascular proliferative lesions. Lancet. 1988 Jun 18;1(8599):1353–1356. doi: 10.1016/s0140-6736(88)92177-0. [DOI] [PubMed] [Google Scholar]
  33. Rönnstrand L., Terracio L., Claesson-Welsh L., Heldin C. H., Rubin K. Characterization of two monoclonal antibodies reactive with the external domain of the platelet-derived growth factor receptor. J Biol Chem. 1988 Jul 25;263(21):10429–10435. [PubMed] [Google Scholar]
  34. Sasahara M., Fries J. W., Raines E. W., Gown A. M., Westrum L. E., Frosch M. P., Bonthron D. T., Ross R., Collins T. PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model. Cell. 1991 Jan 11;64(1):217–227. doi: 10.1016/0092-8674(91)90223-l. [DOI] [PubMed] [Google Scholar]
  35. Schlingemann R. O., Rietveld F. J., Kwaspen F., van de Kerkhof P. C., de Waal R. M., Ruiter D. J. Differential expression of markers for endothelial cells, pericytes, and basal lamina in the microvasculature of tumors and granulation tissue. Am J Pathol. 1991 Jun;138(6):1335–1347. [PMC free article] [PubMed] [Google Scholar]
  36. Shiraishi T., Morimoto S., Itoh K., Sato H., Sugihara K., Onishi T., Ogihara T. Radioimmunoassay of human platelet-derived growth factor using monoclonal antibody toward a synthetic 73-97 fragment of its B-chain. Clin Chim Acta. 1989 Sep 15;184(1):65–74. doi: 10.1016/0009-8981(89)90257-x. [DOI] [PubMed] [Google Scholar]
  37. Siegbahn A., Hammacher A., Westermark B., Heldin C. H. Differential effects of the various isoforms of platelet-derived growth factor on chemotaxis of fibroblasts, monocytes, and granulocytes. J Clin Invest. 1990 Mar;85(3):916–920. doi: 10.1172/JCI114519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Smits A., Hermansson M., Nistér M., Karnushina I., Heldin C. H., Westermark B., Funa K. Rat brain capillary endothelial cells express functional PDGF B-type receptors. Growth Factors. 1989;2(1):1–8. doi: 10.3109/08977198909069076. [DOI] [PubMed] [Google Scholar]
  39. Smits A., Kato M., Westermark B., Nistér M., Heldin C. H., Funa K. Neurotrophic activity of platelet-derived growth factor (PDGF): Rat neuronal cells possess functional PDGF beta-type receptors and respond to PDGF. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8159–8163. doi: 10.1073/pnas.88.18.8159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sorkin A., Westermark B., Heldin C. H., Claesson-Welsh L. Effect of receptor kinase inactivation on the rate of internalization and degradation of PDGF and the PDGF beta-receptor. J Cell Biol. 1991 Feb;112(3):469–478. doi: 10.1083/jcb.112.3.469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Terracio L., Rönnstrand L., Tingström A., Rubin K., Claesson-Welsh L., Funa K., Heldin C. H. Induction of platelet-derived growth factor receptor expression in smooth muscle cells and fibroblasts upon tissue culturing. J Cell Biol. 1988 Nov;107(5):1947–1957. doi: 10.1083/jcb.107.5.1947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tingström A., Reuterdahl C., Lindahl P., Heldin C. H., Rubin K. Expression of platelet-derived growth factor-beta receptors on human fibroblasts. Regulation by recombinant platelet-derived growth factor-BB, IL-1, and tumor necrosis factor-alpha. J Immunol. 1992 Jan 15;148(2):546–554. [PubMed] [Google Scholar]
  43. Wilcox J. N., Smith K. M., Williams L. T., Schwartz S. M., Gordon D. Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest. 1988 Sep;82(3):1134–1143. doi: 10.1172/JCI113671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yeh H. J., Ruit K. G., Wang Y. X., Parks W. C., Snider W. D., Deuel T. F. PDGF A-chain gene is expressed by mammalian neurons during development and in maturity. Cell. 1991 Jan 11;64(1):209–216. doi: 10.1016/0092-8674(91)90222-k. [DOI] [PubMed] [Google Scholar]

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