Competitors race during the Paddle to Battle MS stand up paddle boarding race at Collaroy Beach on March 16, 2024 in Sydney, Australia.(Getty Images/Cameron Spencer)
Researchers from two US universities, Stanford, California and Case Western Reserve University, Ohio, respectively, published two independent research studies in Nature Biotechnology on the 14th of April, showing methods to reprogram differentiated skin cells into specialized functional brain cells that could be used to treat diseases of the central nervous system, such as multiple sclerosis, Pelizaeus-Merzbacher disease or other myelin disorders.
Myelin is a layer surrounding the axons of our neurons and provides electrical insulation. Without the myelin layer (myelin sheath), the electrical current generated by the brain does not propagate easily along the axon; therefore, the nervous system is defective. Myelin in the central nervous system is supplied by oligodendrocytes, which in Greek means “cells with few branches”. If these brain cells are not able to generate myelin, hence insulation, several diseases arise. The source of these cells is the oligodendrocyte precursor cells (OPC), a type of partially differentiated cells which can differentiate into few other types of brain cells. Therefore, scientists believe that transplantation of OPCs, is a feasible treatment strategy for myelin disorders that can reverse myelination. However, where and how we can find functional oligodendrocyte precursor cells is yet unknown or ineffective.
The research team of Marnius Wernig of Stanford University took a particular type of mouse skin cells, mouse embryonic fibroblasts (MEFs), which are abundantly found in the body and are easily prepared, and they added 3 proteins which main function is to regulate the expression of other genes (transcription factors). When they cultured these MEFs in medium specific for oligodendritic cells, they saw that they induced the characteristics of oligodendrocyte precursor cells (OPC) and named them induced OPCs (iOPC). When iOPCs were left to differentiate in the culture, they differentiated in myelin-producing oligodendrocytes. Interestingly, that was not only in vitro. They transplanted iOPC cells in mouse models whose axons are dysmyelinated (as are the axons of patients of multiple sclerosis, etc.) and soon after, some tube-like structures by cells able to generate myelin were observed. They concluded that iOPC cells originated by fibroblasts can generate oligodendrocytes that can myelinate axons in mouse brains.
The second study conducted independently by Najm and colleagues in the group of Paul Tesar, assistant professor at School of Medicine, Case Western Reserve University, Cleveland, U.S., showed something very similar: that adding 3 transcription factors can transform MEFs into myelinating oligodendrocytes. These authors have performed experiments in vivo, too, and they have further shown that iOPCs can be generated, in addition to MEFs, from other somatic cells, that of mouse lung fibroblasts.
Both studies overcame the need to generate induced pluripotent stem (iPS) cells and then differentiate them into brain cells. Here, they directly transform skin cells into functional OPCs reducing largely the time of the experiment. “We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy,” Tesar explains.
The results and the reproducibility are noteworthy and what is remarkable is that 2 of the 3 transcription factors used in both studies, Sox10 and Olig2, are identical. The third factor was different in each study, raising the questions if there are points in which these techniques can be optimized and if one study has something to teach to the other.
However, it is reasonable to expect that one of the next experiments will be to use human fibroblast and test if they can be reprogrammed into human iOPCs, which can eventually be transplanted in patients’ brains unable to produce myelin.
Young and colleagues, predict “that generation of human iOPCs is possible” and that “substantial optimization will likely be required to reliably generate large numbers of iOPCs from human cells”. These are main considerations that need to be resolved before we start talking about cure of diseases of myelin in the central nervous system.
