title: Expression of plasminogen activator inhibitor-1 by olfactory ensheathing glia promotes axonal regeneration.
abstract: Olfactory ensheathing glia (OEG) cells are known to facilitate repair following axotomy of adult neurons, although the molecular mechanisms involved are not fully understood. We previously identified plasminogen activator inhibitor-1 (PAI-1), proteinase-activated receptor-1 (PAR-1), and thrombomodulin (TM) as candidates to regulate rat OEG-dependent axonal regeneration. In this study, we have validated the involvement of these proteins in promoting axonal regeneration by immortalized human OEGs. We studied the effect of silencing these proteins in OEGs on their capacity to promote the regeneration of severed adult retinal ganglion cells (RGCs) axons. Our results support the role of glial PAI-1 as a downstream effector of PAR-1 in promoting axon regeneration. In contrast, we found that TM inhibits OEG induced-axonal regeneration. We also assessed the signaling pathways downstream of PAR-1 that might modulate PAI-1 expression, observing that specifically inhibiting Gα(i), Rho kinase, or PLC and PKC downregulated the expression of PAI-1 in OEGs, with a concomitant reduction in OEG-dependent axon regeneration in adult RGCs. Our findings support an important role for the thrombin system in regulating adult axonal regeneration by OEGs.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Simón
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Martín-Bermejo
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Gallego-Hernández
authors.forename: Erika
authors.initials: E
authors.lastname: Pastrana
authors.forename: Vega
authors.initials: V
authors.lastname: García-Escudero
authors.forename: Ana
authors.initials: A
authors.lastname: García-Gómez
authors.forename: Filip
authors.initials: F
authors.lastname: Lim
authors.forename: Javier
authors.initials: J
authors.lastname: Díaz-Nido
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Moreno-Flores
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D019771:Axotomy / Q000009:adverse effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D009414:Nerve Growth Factors / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009457:Neuroglia / Q000737:chemistry / Q000378:metabolism*; D009830:Olfactory Bulb / Q000166:cytology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D044463:Receptor, PAR-1 / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018180:Thrombomodulin / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D017077:Culture Media, Conditioned; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D018180:Thrombomodulin