title: Induction of oligodendrocyte differentiation and in vitro myelination by inhibition of rho-associated kinase.
abstract: In inflammatory demyelinating diseases such as multiple sclerosis (MS), myelin degradation results in loss of axonal function and eventual axonal degeneration. Differentiation of resident oligodendrocyte precursor cells (OPCs) leading to remyelination of denuded axons occurs regularly in early stages of MS but halts as the pathology transitions into progressive MS. Pharmacological potentiation of endogenous OPC maturation and remyelination is now recognized as a promising therapeutic approach for MS. In this study, we analyzed the effects of modulating the Rho-A/Rho-associated kinase (ROCK) signaling pathway, by the use of selective inhibitors of ROCK, on the transformation of OPCs into mature, myelinating oligodendrocytes. Here we demonstrate, with the use of cellular cultures from rodent and human origin, that ROCK inhibition in OPCs results in a significant generation of branches and cell processes in early differentiation stages, followed by accelerated production of myelin protein as an indication of advanced maturation. Furthermore, inhibition of ROCK enhanced myelin formation in cocultures of human OPCs and neurons and remyelination in rat cerebellar tissue explants previously demyelinated with lysolecithin. Our findings indicate that by direct inhibition of this signaling molecule, the OPC differentiation program is activated resulting in morphological and functional cell maturation, myelin formation, and regeneration. Altogether, we show evidence of modulation of the Rho-A/ROCK signaling pathway as a viable target for the induction of remyelination in demyelinating pathologies.
authors.affiliation: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA carlos.pedraza@emdserono.com.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Pedraza
authors.affiliation: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Taylor
authors.affiliation: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA.
authors.forename: Albertina
authors.initials: A
authors.lastname: Pereira
authors.affiliation: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Seng
authors.affiliation: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA.
authors.forename: Chui-Se
authors.initials: CS
authors.lastname: Tham
authors.affiliation: Kadimastem, Ness Ziona, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Izrael
authors.affiliation: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Webb
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D009836:Oligodendroglia; D009900:Optic Nerve / Q000166:cytology; D051381:Rats; D013234:Stem Cells; D013997:Time Factors; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D020932:Nerve Growth Factor; D054460:rho-Associated Kinases
keywords: ROCK inhibition; cytoskeletal dynamics; human OPCs; maturation; myelin regeneration; oligodendrocytes