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Hepatocyte growth factor effects on mesenchymal stem cells Proliferation.pdf

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Hepatocyte growth factor effects on mesenchymal stem cells Proliferation

Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells: Proliferation, Migration, and Differentiation GIANCARLO FORTE,a MARILENA MINIERI,a PAOLO COSSA,a DANIELE ANTENUCCI,a MARILENA SALA,b VIOLA GNOCCHI,b ROBERTA FIACCAVENTO,a FELICIA CAROTENUTO,a PAOLO DE VITO,c PATRIZIA MORENA BALDINI,c MARIA PRAT,b PAOLO DI NARDOa aMolecular and Cellular Cardiology Lab, Department of Internal Medicine, University of Rome “Tor Vergata,” Italy. bDepartment of Medical Sciences, University “A. Avogadro” of Piemonte Orientale, Novara, Italy. cDepartment of Biology, University of Rome “Tor Vergata,” Italy Key Words. Met receptor ? Mesenchymal stem cells ? Hepatocyte growth factor ? p38 ? Akt ABSTRACT Hepatocyte growth factor (HGF), a pleiotropic cytokine of mesenchymal origin promoting migration, prolifera- tion, and survival in a wide spectrum of cells, can also modulate different biological responses in stem cells, but the mechanisms involved are not completely understood so far. In this context, we show that short-term exposure of mesenchymal stem cells (MSCs) to HGF can induce the activation of its cognate Met receptor and the down- stream effectors ERK1/2, p38MAPK, and PI3K/Akt, while long-term exposure to HGF resulted in cytoskeletal rearrangement, cell migration, and marked inhibition of proliferation through the arrest in the G1-S checkpoint. When added to MSCs, the K252A tyrosine kinase inhib- itor prevented HGF-induced responses. HGF’s effect on MSC proliferation was reversed by p38 inhibitor SB203580, while the effects on cell migration were abro- gated by PI3K inhibitor Wortmannin, suggesting that HGF acts through different pathways to determine its complex effects on MSCs. Prolonged treatment with HGF induced the expression of cardiac-specific markers (GATA-4, MEF2C, TEF1, desmin, -MHC, -MHC, and nestin) with the concomitant loss of the stem cell markers nucleostemin, c-kit, and CD105. STEM CELLS 2006;24: 23–33 INTRODUCTION Bone marrow mesenchymal stem cells (MSCs) d