Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation.
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-term exposure of mesenchymal stem cells (MSCs) to HGF can induce the activation of its cognate Met receptor and the downstream 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 inhibitor prevented HGF-induced responses. HGF's 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 MSCs. Prolonged treatment with HGF induced the expression of cardiac-specific markers (GATA-4, MEF2C, TEF1, desmin, alpha-MHC, beta-MHC, and nestin) with the concomitant loss of the stem cell markers nucleostemin, c-kit, and CD105.
Forte
Giancarlo
G
Molecular and Cellular Lab, Dipartimento di Medicina Interna, Università di Roma Tor Vergata, Via Montpellier, 1, 00133 Roma, Italy.
Minieri
Marilena
M
Cossa
Paolo
P
Antenucci
Daniele
D
Sala
Marilena
M
Gnocchi
Viola
V
Fiaccavento
Roberta
R
Carotenuto
Felicia
F
De Vito
Paolo
P
Baldini
Patrizia Morena
PM
Prat
Maria
M
Di Nardo
Paolo
P
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006321:Heart / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases