Development of a Chemical Cocktail That Rescues Mouse Brain Demyelination in a Cuprizone-Induced Model
Journal
Cells
Journal Volume
11
Journal Issue
7
Date Issued
2022
Author(s)
Lai P.-L
Ng C.-H
Wu C.-H
Lai C.-Y
Schuyler S.C
Wang V
Lin H
Lee Y.-C
Chuang M.-H
Yang C.-H
Chen W.-J
Lu J.
Abstract
Oligodendrocytes are glial cells located in the central nervous system (CNS) that play essential roles in the transmission of nerve signals and in the neuroprotection of myelinated neurons. The dysfunction or loss of oligodendrocytes leads to demyelinating diseases such as multiple sclerosis (MS). To treat demyelinating diseases, the development of a therapy that promotes remyelination is required. In the present study, we established an in vitro method to convert human fibroblasts into induced oligodendrocyte-like cells (iOLCs) in 3 days. The induced cells displayed morphologies and molecular signatures similar to oligodendrocytes after treatment with valproic acid and exposure to the small molecules Y27632, SU9516, and forskolin (FSK). To pursue the development of a cell-free remyelination therapy in vivo, we used a cuprizone-induced demyelinated mouse model. The small molecules (Y27632, SU9516, and FSK) were directly injected into the demyelinated corpus callosum of the mouse brain. This combination of small molecules rescued the demyelination phenotype within two weeks as observed by light and electron microscopy. These results provide a foundation for exploring the development of a treatment for demyelinating diseases via regenerative medicine. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Subjects
Cuprizone-induced model; Demyelination; Induced oligodendrocyte-like cells (iOLCs); Multiple sclerosis (MS); Oligodendrocyte progenitor cells (OPCs); Oligodendrocytes; Remyelination
SDGs
Other Subjects
4 (1 aminoethyl) n (4 pyridyl)cyclohexanecarboxamide; chemical compound; cuprizone; cyclin dependent kinase inhibitor; epidermal growth factor; fibroblast growth factor; forskolin; galactosylceramidase; glutaraldehyde; histone deacetylase inhibitor; neurotrophin 3; oligodendrocyte transcription factor 2; paraformaldehyde; phosphate buffered saline; platelet derived growth factor; protein; proteolipid protein; proteolipid protein 1; Rho kinase; su9516 protein; tiletamine plus zolazepam; unclassified drug; valproic acid; animal model; animal tissue; Article; cell viability; controlled study; demyelinating disease; demyelination; fibroblast; fluorescence microscopy; heart perfusion; human; human cell; immunofluorescence assay; induced pluripotent stem cell; mouse; multiple sclerosis; nonhuman; nuclear reprogramming; oligodendrocyte precursor cell; real time reverse transcription polymerase chain reaction; regenerative medicine; remyelinization; transmission electron microscopy; Western blotting
Type
journal article