Koji Tanabe of I Peace, Inc. (https://www.ipeace.com) and a researcher Hiroko Nobuta of the University of California, San Francisco (currently assistant professor at Rutgers University) successfully achieved the direct reprogramming: the direct and rapid transformation of Dermal fibroblasts into Oligodendrocyte precursor cells by inducing four genes into the cells. This research was jointly conducted with Prof. Wernig at Sanford University and Prof. Rowitch at UCSF. The research was published in the online edition of an academic journal “Development” on June 24th.
Oligodendrocytes are cells that form myelin around the axons of neurons, which act as insulators surrounding the neurons and accelerate the rate at which electrical signals flow. Abnormalities in oligodendrocytes cause cerebral leukodystrophy. The production of a large number of oligodendrocytes is necessary for understanding its pathology, drug discovery, and transplantation medicine. The conventional method of inducing differentiation of human iPS cells or ES cells into oligodendrocytes is inefficient and requires a long time for differentiation induction. Therefore, it has required high cost for the transplantation medicine and the clarification of the pathology, which hinder the development for early treatment and drug discovery. In addition, transplantation treatment has accompanied with problems such as the possibility of tumor formation due to contamination of undifferentiated cells.
In this study, we have successfully transformed dermal cells into oligodendrocyte precursors without undergoing the stem cell state. Surprisingly, oligodendrocyte precursors produced directly from dermal cells finally differentiated into functional oligodendrocytes that wrapped around neurons to form myelin sheaths both in vitro and in vivo mouse brain after transplantation. Furthermore, we successfully reproduced the clinical condition in vitro using oligodendrocyte precursors cells generated from dermal cells of a patient with Pelizaeus-Merzbacher disease (PMD), a type of congenital myelination failure. PMD is a developmental disorder that occurs in children and is caused by an abnormality in the oligodendrocyte specific gene PLP1. It is known that the gene abnormality causes oligodendrocytes to die in the brain during differentiation, which prevents myelination. At present, there is no fundamental treatment for the disease, with only palliative treatment for symptoms such as movement impairment, spastic paralysis, and epilepsy. The direct reprogramming from this study successfully reproduced the pathological condition within a significantly reduced production time, which will surely accelerate drug discovery and development in the future.
The oligodendrocyte precursor cells produced in this study have been proven to engraft in the mouse brain after transplantation and wrap around neurons. Therefore, they are expected to be technically applied to transplantation regenerative medicine for other congenital myelination failure disorders and myelinopathy (multiple sclerosis, optic neuromyelitis, etc.) which effective treatments are rare.
The link to the article published in the journal Development is as follows:
The Rowitch and Wernig labs have declared no financial interest in the company and that the company did not fund the research.
Researcher Hiroko Nobuta established a laboratory at Rutgers University in New Jersey in September 2020. She works for drug discovery and regeneration research for myelin diseases using oligodendrocytes created by the direct programming.