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dc.contributor.authorTanabe, Koji
dc.contributor.authorNobuta, Hiroko
dc.contributor.authorYang, Nan
dc.contributor.authorAng, Cheen Euong
dc.contributor.authorHuie, Philip
dc.contributor.authorJordan, Sacha
dc.contributor.authorOldham, Michael C
dc.contributor.authorRowitch, David H
dc.contributor.authorWernig, Marius
dc.date.accessioned2022-06-29T19:45:22Z
dc.date.available2022-06-29T19:45:22Z
dc.date.issued2022-10-15
dc.date.submitted2021-04-21
dc.identifier.issn0950-1991
dc.identifier.otherdev199723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338502
dc.descriptionFunder: National Multiple Sclerosis Society; Id: http://dx.doi.org/10.13039/100000890
dc.descriptionFunder: Association Européenne contre les Leucodystrophies; Id: http://dx.doi.org/10.13039/501100008731
dc.descriptionFunder: New York Stem Cell Foundation; Id: http://dx.doi.org/10.13039/100003194
dc.descriptionFunder: University of California, San Francisco; Id: http://dx.doi.org/10.13039/100008069
dc.descriptionFunder: Sandler Foundation; Id: http://dx.doi.org/10.13039/100007100
dc.descriptionFunder: Action Medical Research; Id: http://dx.doi.org/10.13039/501100000317
dc.descriptionFunder: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Id: http://dx.doi.org/10.13039/100005984
dc.descriptionFunder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272
dc.descriptionFunder: Stanford University; Id: http://dx.doi.org/10.13039/100005492
dc.descriptionFunder: Foundation Optic Atrophy 1
dc.description.abstractOligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols ( Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts.
dc.languageen
dc.publisherThe Company of Biologists
dc.subjecthuman development
dc.subjectstem cells & regeneration
dc.subjectHUMAN DEVELOPMENT
dc.subjectDirect lineage conversion
dc.subjectOligodendrocyte
dc.subjectLeukodystrophy
dc.subjectMyelination
dc.subjectFibroblasts
dc.subjectHuman
dc.titleGeneration of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion.
dc.typeArticle
dc.date.updated2022-06-29T19:45:22Z
prism.issueIdentifier20
prism.publicationNameDevelopment
prism.volume149
dc.identifier.doi10.17863/CAM.85915
dcterms.dateAccepted2022-05-03
rioxxterms.versionofrecord10.1242/dev.199723
rioxxterms.versionAO
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0
dc.contributor.orcidNobuta, Hiroko [0000-0003-1410-2086]
dc.contributor.orcidAng, Cheen Euong [0000-0002-9050-6122]
dc.contributor.orcidWernig, Marius [0000-0002-5309-515X]
dc.identifier.eissn1477-9129
pubs.funder-project-idEuropean Research Council (789054)
cam.issuedOnline2022-06-24


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