title: Role of matrix metalloproteinases in migration and neurotrophic properties of nasal olfactory stem and ensheathing cells.
abstract: Adult olfactory ectomesenchymal stem cells (OE-MSCs) and olfactory ensheathing cells (OECs), both from the nasal olfactory lamina propria, display robust regenerative properties when transplanted into the nervous system, but the mechanisms supporting such therapeutic effects remain unknown. Matrix metalloproteinases (MMPs) are an important family of proteinases contributing to cell motility and axonal outgrowth across the extracellular matrix (ECM) in physiological and pathological conditions. In this study, we have characterized for the first time in nasal human OE-MSCs the expression profile of some MMPs currently associated with cell migration and invasiveness. We demonstrate different patterns of expression for MMP-1, MMP-2, MMP-9, and MT1-MMP upon cell migration when compared with nonmigrating cells. Our results establish a correspondence between the localization of these proteinases in the migration front with the ability of cells to migrate. Using various modulators of MMP activity, we also show that at least MMP-2, MMP-9, and MT1-MMP contribute to OE-MSC migration in an in vitro 3D test. Furthermore, we demonstrate under the same conditions of culture used for in vivo transplantation that OE-MSCs and OECs secrete neurotrophic factors that promote neurite outgrowth of cortical and dorsal root ganglia (DRG) neurons, as well as axo-dendritic differentiation of cortical neurons. These effects were abolished by the depletion of MMP-2 and MMP-9 from the culture conditioned media. Altogether, our results provide the first evidence that MMPs may contribute to the therapeutic features of OE-MSCs and OECs through the control of their motility and/or their neurotrophic properties. Our data provide new insight into the mechanisms of neuroregeneration and will contribute to optimization of cell therapy strategies.
authors.affiliation: Aix-Marseille Univ, Neurobiologie des Interactions Cellulaires et Neurophysiopathologie (NICN), UMR 7259, 13344, Marseille, France.
authors.forename: Adlane
authors.initials: A
authors.lastname: Ould-Yahoui
authors.forename: Oualid
authors.initials: O
authors.lastname: Sbai
authors.forename: Kévin
authors.initials: K
authors.lastname: Baranger
authors.forename: Anne
authors.initials: A
authors.lastname: Bernard
authors.forename: Yatma
authors.initials: Y
authors.lastname: Gueye
authors.forename: Eliane
authors.initials: E
authors.lastname: Charrat
authors.forename: Benoît
authors.initials: B
authors.lastname: Clément
authors.forename: Didier
authors.initials: D
authors.lastname: Gigmes
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.forename: Stéphane D
authors.initials: SD
authors.lastname: Girard
authors.forename: François
authors.initials: F
authors.lastname: Féron
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
authors.forename: Santiago
authors.initials: S
authors.lastname: Rivera
mesh_terms: D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005780:Gelatin / Q000378:metabolism; D006801:Humans; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009666:Nose / Q000166:cytology*; D009830:Olfactory Bulb / Q000166:cytology*; D051381:Rats; D011917:Rats, Inbred Lew; D055815:Young Adult
chemical_list: D017077:Culture Media, Conditioned; D061965:Matrix Metalloproteinase Inhibitors; D009414:Nerve Growth Factors; D005780:Gelatin; D020782:Matrix Metalloproteinases