Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells: Proliferation, Migration and Differentiation

¹ Laboratorio di Cardiologia Molecolare e Cellulare, Dipartimento di Medicina Interna, Università di Roma "Tor Vergata", Roma, Italy
² Dipartimento di Scienze Mediche, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
³ Dipartimento di Biologia, Università di Roma "Tor Vergata", Roma, Italy

^* To whom correspondence should be addressed. E-mail: dinardo{at}med.uniroma2.it.

	Abstract

Hepatocyte Growth Factor (HGF), a pleiotropic cytokine of mesenchymal origin promoting migration, proliferation 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 time exposure of Mesenchymal Stem Cells (MSC) to HGF, can induce the activation of its cognate Met receptor and the downstream effectors ERK1/2, p38MAPK and PI3K/Akt, while long-time 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 MSC, the K252A tyrosine kinase inhibitor prevented HGF-induced responses. HGF effect on MSC proliferation was reversed by p38 inhibitor SB203580, while the effects on cell migration were abrogated by PI3K inhibitor Wortmannin, suggesting that HGF acts through different pathways to determine its complex effects on MSC. 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.

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