Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitors Remyelinate the Brain and Rescue Behavioral Deficits following Radiation

Radiation therapy to the brain is a powerful tool in the management of many cancers, but it is associated with significant and irreversible long-term side effects, including cognitive decline and impairment of motor coordination. Depletion of oligodendrocyte progenitors and demyelination are major p...

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Published in:Cell stem cell 2015-02, Vol.16 (2), p.198-210
Main Authors: Piao, Jinghua, Major, Tamara, Auyeung, Gordon, Policarpio, Edelweiss, Menon, Jayanthi, Droms, Leif, Gutin, Philip, Uryu, Kunihiro, Tchieu, Jason, Soulet, Denis, Tabar, Viviane
Format: Article
Language:English
Subjects:
Animals
Brain - cytology
Brain - physiopathology
Brain - radiation effects
Cognition Disorders - etiology
Cognition Disorders - physiopathology
Cognition Disorders - therapy
Disease Models, Animal
Female
Human Embryonic Stem Cells - cytology
Humans
Myelin Sheath - metabolism
Oligodendroglia - cytology
Oligodendroglia - transplantation
Rats
Rats, Nude
X-Rays
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Summary:Radiation therapy to the brain is a powerful tool in the management of many cancers, but it is associated with significant and irreversible long-term side effects, including cognitive decline and impairment of motor coordination. Depletion of oligodendrocyte progenitors and demyelination are major pathological features that are particularly pronounced in younger individuals and severely limit therapeutic options. Here we tested whether human ESC-derived oligodendrocytes can functionally remyelinate the irradiated brain using a rat model. We demonstrate the efficient derivation and prospective isolation of human oligodendrocyte progenitors, which, upon transplantation, migrate throughout the major white matter tracts resulting in both structural and functional repair. Behavioral testing showed complete recovery of cognitive function while additional recovery from motor deficits required concomitant transplantation into the cerebellum. The ability to repair radiation-induced damage to the brain could dramatically improve the outlook for cancer survivors and enable more effective use of radiation therapies, especially in children. [Display omitted] •A clinical dose of brain radiation induces demyelination and behavioral deficits•Oligodendrocyte progenitors (hOPC) are derived from human pluripotent stem cells•hOPCs grafted in the forebrain remyelinate the brain and rescue cognitive deficits•hOPC grafts in the cerebellum are required for improvement in motor tasks Radiation injury to the brain remains a common problem among cancer survivors, leading to significant deterioration in quality of life. A key long-term consequence of radiation is diffuse demyelination. Piao et al. derive oligodendrocyte progenitors from hPSCs and demonstrate that engrafted cells restore myelination and behavioral defects of irradiated rats.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2015.01.004