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Embryonic Stem Cells Reveal Clues About Myelin

Development, April 9, 2009

Scientists in the Departments of Anatomy and Neurology at the School of Medicine and Public Health at the University of Wisconsin at Madison have reported the successful formation of oligodendrocytes from human embryonic stem cells (hESCs), with a few surprising discoveries.

Within the human central nervous system (CNS), oligodendrocytes are the neuroglia that are responsible for forming myelin, which is the dielectric, electrically insulating fatty sheath that covers the axons of neurons throughout the entire body, and which is essential for the transmission of electrical signals along nerve fibers. While Schwann cells supply myelin to the axons of peripheral nerves, oligodendrocytes supply myelin exclusively to the axons of the CNS, and several demyelinating diseases such as, most notably, multiple sclerosis, are a result of the deterioration of the myelin that ordinarily is found within the CNS. Although degenerative conditions such as multiple sclerosis are known as "demyelinating" diseases, the problem is primarily with the oligodendrocytes, and secondarily with the myelin. Since myelin is approximately 80% lipid and 20% protein, nutrition is also known to play a crucial role in the maintenance of healthy myelin.

In the past, laboratory researchers have encountered a number of frustrating difficulties when trying to coax hESCs into oligodendrocytes, despite the fact that it has always been relatively easy to differentiate oligodendrocytes from mouse ESCs (mESCs). In mice, the production of oligodendrocytes is accomplished by exposure of the mESCs to a protein known as "sonic hedgehog homolog" (SHH), a ligand in the murine signaling pathway and a morphogen that has been well described in the regulation of vertebrate organogenesis and neurological organization. In hESCs, however, exposure to SHH was not enough to generate oligodendrocytes. As an aside, it is interesting to note that a number of scientists and clinicians alike continue to criticize the name of this homolog, which is an evolution of the original "hedgehog" gene that was first discovered in Drosophila melanogaster (the fruit fly) and which resulted in pointed projections that formed on the surface of Drosophila embryos whenever the gene was absent or inactivated, thereby resembling a hedgehog appearance in the embryos, which thus inspired the name. For discovering the hedgehog gene, Drs. Eric Wieschaus, Christiane Nusslein-Volhard and Edward B. Lewis were awarded the 1995 Nobel Prize in Physiology or Medicine. Currently 3 proteins have been identified in the mammalian "hedgehog" family, the other 2 besides SHH being "desert hedgehog" (DHH) and Indian hedgehog (IHH).

Now, Dr. Su-Chun Zhang and his colleagues at the University of Wisconsin at Madison may have discovered some of the reasons for the difficulties that scientists have typically encountered when trying to differentiate oligodendrocytes from hESCs. Among other things, the scientists found that exposure of the hESCs to SHH will, in fact, still result in the differentiation of the hESCs into oligodendrocytes, even though the differentiation process requires 14 weeks for hESCs as opposed to merely 2 weeks with mESCs. Paradoxically, however, one of the growth factors that promotes the differentiation of mESCs into oligodendrocytes, namesly, Fgf2 (fibroblast growth factor 2, also known as "basic fibroblast growth factor", one of the 22 members of the structurally signaling molecules that comprise the FGF family), was surprisngly found to inhibit the differentiation in hESCs. Although Fgf2 has been known to play a key role in keeping hESCs in an undifferentiated state, the precise mechanisms by which this occurs have not yet been elucidated, nor is it understood exactly how Fgf2 promotes differentiation in mESCs.

As Dr. Zhang explains, "This was quite a surprise given that this is exactly how we direct mouse ESCs to become oligodendrocytes. But we have discovered an unexpected twist in the cell's response to the same external factor. It nevertheless explains why so many research groups have failed to persuade human neural stem cells to become oligodendrocytes for the past decade."

Dr. Zhang adds, "We are now able to generate a relatively enriched population of oligodendrocyte precursor cells that may be used to repair lost myelin sheaths. These findings also raise awareness of the direct translatability of animal studies to human biology. In this regard, the human oligodendrocytes generated from human ESCs of disease-induced pluripotent stem cells can provide a useful tool in the future for screening pharmaceuticals directly on human cells."

Given the complexities inherent in the differentiation process from hESCs, and the uncertainties that still remain in controlling this process, it is therefore all the more impressive that other doctors and scientists, in studies unrelated to that of Dr. Zhang's, have already achieved significant improvement in human multiple sclerosis patients using adult, not embryonic, stem cells. (Please see the related article on this website, entitled, "Adult Stem Cells From Fat Help Multiple Sclerosis Patients", dated April 24, 2009, as reported in the Journal of Translational Medicine).

Indeed, with numerous patients throughout the world who need treatment now, today - not ten years from now, nor even one year from now, nor even one month from now - the need for a viable clinical stem cell therapy for diseases and injuries grows increasingly urgent. While discoveries such as Dr. Zhang's are extremely interesting from a scientific point of view, they offer little that is immediately translatable to the clinic, from a therapeutic point of view. For medical therapies that are already being used in real clinics by real doctors on real human patients with real human diseases, today, at this very moment, adult stem cells are the only stem cells that already constitute any type of clinical therapy.



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