title: Thrombin-activated platelets induce proliferation of human skin fibroblasts by stimulating autocrine production of insulin-like growth factor-1.
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.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Via Pansini 5, 80131 Napoli, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Giacco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perruolo
authors.forename: Elio
authors.initials: E
authors.lastname: D'Agostino
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fratellanza
authors.forename: Enzo
authors.initials: E
authors.lastname: Perna
authors.forename: Saverio
authors.initials: S
authors.lastname: Misso
authors.forename: Gennaro
authors.initials: G
authors.lastname: Saldalamacchia
authors.forename: Francesco
authors.initials: F
authors.lastname: Oriente
authors.forename: Francesca
authors.initials: F
authors.lastname: Fiory
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
authors.forename: Salvatore
authors.initials: S
authors.lastname: Formisano
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
mesh_terms: D001792:Blood Platelets / Q000166:cytology / Q000502:physiology*; D018929:Cell Culture Techniques; D002455:Cell Division; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D015539:Platelet Activation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012867:Skin / Q000166:cytology; D012879:Skin Physiological Phenomena; D013917:Thrombin / Q000502:physiology*
chemical_list: D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin