Thrombin-activated platelets induce proliferation of human skin fibroblasts by stimulating autocrine production of insulin-like growth factor-1

Ferdinando Giacco, Giuseppe Perruolo, Elio D'Agostino, Giorgio Fratellanza, Enzo Perna, Saverio Misso, Gennaro Saldalamacchia, Francesco Oriente, Francesca Fiory, Claudia Miele, Salvatore Formisano, Francesco Beguinot, Pietro Formisano

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28 Scopus citations

Abstract

Platelet components have found successful clinical utilization to initiate or to accelerate tissue-repair mechanisms. However, the molecular pathways by which platelet factors contribute to tissue regeneration have not been fully elucidated. We have studied the effect of thrombin-activated platelets (TAPs) on cell growth in vivo and in cultured cell systems. Application of TAPs to ulcerative skin lesions of diabetic patients induced local activation of ERK1/2 and Akt/PKB. Moreover, when applied to cultured human skin fibroblasts, TAPs promoted cell growth and DNA synthesis and activated platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF)-1 receptor tyrosine kinases. PDGF was released by TAPs and rapidly achieved a plateau. At variance, the release of IGF-1 was mainly provided by the TAPs-stimulated fibroblasts and progressively increased up to 48 h. The PDGF-R blocker Ag1296 reduced the activation of Akt/PKB and, at a lesser extent, of ERK1/2. Conversely, inhibition of IGF-1 signaling by Ag1024 and expression of a dominant-negative IGF-1R mutant selectively reduced the stimulation of ERK1/2 by TAPs and fibroblast-released factors, with minor changes of Akt/PKB activity. Thus, platelet factors promote fibroblast growth by acutely activating Akt/PKB and ERK1/2. Sustained activation of ERK1/2, however, requires autocrine production of IGF-1 by TAPs-stimulated fibroblasts.

Original languageEnglish (US)
Pages (from-to)E1763-E1772
JournalFASEB Journal
Volume20
Issue number13
DOIs
StatePublished - Nov 1 2006

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Keywords

  • Akt/PKB
  • Diabetic foot
  • ERK
  • Growth factor receptors
  • Tyrosine kinase

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Giacco, F., Perruolo, G., D'Agostino, E., Fratellanza, G., Perna, E., Misso, S., Saldalamacchia, G., Oriente, F., Fiory, F., Miele, C., Formisano, S., Beguinot, F., & Formisano, P. (2006). Thrombin-activated platelets induce proliferation of human skin fibroblasts by stimulating autocrine production of insulin-like growth factor-1. FASEB Journal, 20(13), E1763-E1772. https://doi.org/10.1096/fj.06-6104fje