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2020-05-24| R&D

Breakthrough Stem Cell Therapy Research Shows Repair in Multiple Sclerosis Damage

by Ruchi Jhonsa
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By Ruchi Jhonsa, Ph.D.

Multiple Sclerosis is a chronic inflammatory disorder of the brain in which the immune system attacks the myelin sheath producing cells known as oligodendrocytes. Disruption of myelin sheath leaves scars on the nerves making it harder for neurons to carry the message. This affects normal motor and sensory functions and hampers day-to-day activities. Currently, there is no definite treatment for the disease. However, immune modulators including Mayzent (Novartis), Zinbryta (Biogen/Abbvie) Aubagio (Sanofi), Zeposia (BMS), and several others are frequently used to slow down the progression of the disease.

Several cell-based therapies are currently under research for the treatment of MS that uses stem cells to restore the oligodendrocyte population. One such research was published in the journal Cell on May 19th. A team led by Dr. Goldman at the University of Rochester Medical Center (URMC) has demonstrated that glial progenitor cells derived from the human fetal brain can restore myelin sheath and neuronal function in an animal model of multiple sclerosis.

The human glial progenitor cells (hGPC) transplanted into an adult mouse model of MS traveled to the brain and manufactured new glial cells and replaced the damaged and missing myelin. Scientists believe that this approach can be extended to other indications such as pediatric leukodystrophies and certain kinds of strokes in adults. The team’s studies are described in a paper titled, “Human Glial Progenitor Cells Effectively Remyelinate the Demyelinated Adult Brain.”

 

What is Unique About this Study?

Inside the human brain, the glial progenitor cells (GPCs) arise from neural stem cells and disperse widely throughout the tissue. They are the principal source of new oligodendrocytes and are responsible for putting myelin on neuronal cells that have lost it. For long, scientists have been trying to harvest the potential of human GPCs in restoring myelination in brain lesions associated with several disease conditions. They successfully showed that injection of human-derived lab-grown hGPCs in the brain can myelinate the nerve cells and improve the lifespan in the demyelinated mouse model.

However, these studies inspected hGPC’s role in focused lesions and did not include diffusely demyelinated tissues in the study. To this end, none of the prior studies have assessed the ability of hGPCs to migrate within the brain tissue. The breakthrough study published by URMC researchers tested the ability of hGPCs to migrate within the brain tissue and restore normal myelin sheath on the demyelinated neurons spread throughout the brain.

 

Human Pluripotent Glial Cells Restore Myelination

To assess the ability of hGPCs to restore myelin coating on the brain cells, the group used a mice mutant called shiverer that lacked myelin from birth. The authors pointed out that this mutant aids in mimicking the conditions of the human brain affected by hypomyelinating leukodystrophy and congenital leukodystrophies.

The study showed that the hGPCs were able to migrate throughout the forebrain of young adult shiverer mice within 2 weeks of injection. Moreover, they differentiated into the type of cell that makes myelin and produced dense myelin coats on the neurons. More importantly, at a 19-week time point, the density of all human cells including hGPCs, oligodendrocytes, and astrocytes were significantly higher than the wildtype control.

 

hGPCs are Effective in Coating Neurons with Myelin in MS Mouse Model

In a different experiment, the group evaluated the activity of hGPCs in mice brains that were stripped of myelin after the coating had developed. This was in contrast to the first experiment where the myelin sheath was absent from the birth of the animal. Authors believe that “this later set of experiments, provided an important proof-of-principle, showing that hGPCs could remyelinate axons that had already been myelinated in the past and that were then demyelinated in the setting of oligodendrocyte loss; precisely such a scenario might be anticipated in disorders such as progressive multiple sclerosis.”

For removing myelin from the neurons, mice were treated with Cuprizone, a compound that causes prominent demyelination in oligodendrocytes. The compound was fed to the mice 4 months after the transplantation of hGPCs. Similar to the previous experiment, the hGPCs dispersed throughout the forebrain, robustly generating new oligodendrocytes, and effectively myelinating the demyelinated neurons. Interestingly, both the total number and the percentage of human cells that differentiated as oligodendrocytes increased significantly faster in Cuprizone treated mice than the non-treated control mice.

 

Remyelination Restored Function of Demyelinated Neurons

Although hGPCs were successful in restoring myelination, it remained to determine whether these neurons can function in the same way as they used to function before. To assess the function, the group did a motor function test on the shiverer mice with and without hGPC transplantation wherein the mice were made to run on a treadmill and the time for which they remained on the moving mill was measured. By 18 weeks, mice with restored myelin showed improved motor function. Out of 8 untreated mice, only 2 were able to remain on the treadmill for 5 s testing period whereas 7 of 8 transplanted shiverer mice were able to do so on their first attempt. These functional improvements were associated with compact myelination and layers of myelin sheets observed at high resolution through an electron microscope.

 

Can this Therapy Work in MS Patients?

Although hGPCs could restore lost myelin in mice, it may or may not work in humans. This is because the effect of the treatment greatly depends on the environment of the brain. MS is an autoimmune condition where the inflammatory response ends up killing oligodendrocytes. The environment of MS brain tissue is highly inflammatory and this can impede the success of cell-based therapies.

Moreover, transplantation with hGPCs can lead to severe complications in these disease conditions as migratory GPCs may flare the inflammatory responses. There are also concerns that GPCs may not be able to remyelinate human brain cells because of the high activity of the Wnt signaling pathway in the brain lesions that block progenitor cells from differentiating into oligodendrocytes. Nonetheless, there is a lot of hope for the therapy. With the current anti-inflammatory treatment regimens, it is possible to control the concern of the inflammatory environment. However, other speculations will be put to rest only with human experiments.

Related Article: Novartis Announces Mayzent Data that Shows Extended Benefit in Secondary Progressive MS

References
  1. https://www.cell.com/cell-reports/pdf/S2211-1247(20)30611-2.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124720306112%3Fshowall%3Dtrue
  2. https://academic.oup.com/brain/article/134/4/1168/343709
  3. https://www.sciencedirect.com/science/article/pii/S1934590915000053
  4. https://www.geneonline.com/2020/04/21/novartis-announces-mayzent-data-that-shows-benefit-in-secondary-progressive-ms/?doing_wp_cron=1590184110.6356990337371826171875
  5. https://www.sciencedirect.com/science/article/pii/S0079612317300110
  6. https://science.sciencemag.org/content/338/6106/491#
  7. https://www.nature.com/articles/nrn.2017.136
  8. https://www.nature.com/articles/nrn2480

 

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