Researchers Succeed at Generating Oligodendrocytes, Key to Myelin Renewal, in Tissue Created in Lab

Researchers Succeed at Generating Oligodendrocytes, Key to Myelin Renewal, in Tissue Created in Lab

Researchers at Case Western Reserve University School of Medicine have developed a cutting-edge laboratory technique able to turn human stem cells – special cells able to grow into any type of cell in the body – into brain-like tissues in a culture dish.

They intend to use their tool to study how myelination – the deposition of myelin around nerve cells – occurs in the central nervous system, and how diseases such as multiple sclerosis (MS) impair this process.

The experimental protocol to grow these structures in vitro (outside an organism) is described in the study, “Induction of myelinating oligodendrocytes in human cortical spheroids,” published in the journal Nature Methods.

These structures, called “oligocortical spheroids,” are small spheres that contain all the major cell types usually found in the human brain, including oligodendrocytes — cells that produce myelin, which is the fatty substance that insulates nerve fibers. Previous cerebral organoid techniques failed to include oligodendrocytes.

“We have taken the organoid system and added the third major cell type in the central nervous system — oligodendrocytes — and now have a more accurate representation of cellular interactions that occur during human brain development,” Paul Tesar, PhD, associate professor of genetics and genome sciences at Case Western’s medical school and the study’s senior author, said in a press release.

Oligodendrocytes are essential to good brain health. Without these cells, myelin production is hampered and nerve cells cannot communicate effectively, and eventually they start to deteriorate. This is the starting point for many neurological disorders caused by myelin defects, including MS and rare pediatric genetic disorders like Gaucher disease.

Using this new organoid system and these myelin-producing cells, researchers intend to study the process of myelination — how it occurs in normal circumstances and how neurodegenerative diseases disrupt this process.

“This is a powerful platform to understand human development and neurological disease,” Tesar said. “Using stem cell technology we can generate nearly unlimited quantities of human brain-like tissue in the lab. Our method creates a ‘mini-cortex,’ containing neurons, astrocytes, and now oligodendrocytes producing myelin. This is a major step toward unlocking stages of human brain development that previously were inaccessible.”

Researchers not only demonstrated that they were capable of generating mature oligodendrocytes derived from human stem cells in vitro, but they also showed these cells were able to exert their function and produce myelin starting at week 20 in a culture dish.

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Their improved organoid system could also be used to test the effectiveness of potential myelin-enhancing treatments.

“These organoids provide a way to predict the safety and efficacy of new myelin therapeutics on human brain-like tissue in the laboratory prior to clinical testing in humans,” said Mayur Madhavan, PhD, co-first author on the study.

To prove this point, researchers treated organoids with promyelinating compounds known to enhance myelin production in mice, and measured the rate and extent of oligodendrocyte generation and myelination.

Under normal conditions, adding promyelinating drugs to cultured organoids increased the rate and extent of oligodendrocyte generation and myelin production, the team reported.

But results differed in important ways using diseased organoids.  Specifically, treating organoids generated from patients with Pelizaeus-Merzbacher disease — a fatal genetic myelin disorder — brought an in vitro recapitulation of the patients’ symptoms.

“Pelizaeus-Merzbacher disease has been a complicated disorder to study due to the many different mutations that can cause it and the inaccessibility of patient brain tissue,” said Zachary Nevin, PhD, co-first author on the study. “But these new organoids allow us to directly study brain-like tissue from many patients simultaneously and test potential therapies.”

Altogether, these findings demonstrate that oligocortical spheroids could be a versatile in vitro system to study how myelination occurs in the central nervous system, and a possible model for testing new therapies for neurodegenerative disorders.

“Our method enables generation of human brain tissue in the laboratory from any patient,” Tesar said. “More broadly, it can accurately recapitulate how the human nervous system is built and identify what goes wrong in certain neurological conditions.”

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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16 comments

  1. Wonderful that our editorship responsibly reports on all positive developments and advances. But, with all due respect to the advances, re-myelination is only part of the picture, don’t you all get it? There are those of us, too many of us of this disease-ridden demographic who crave CURE, who desperately require CURE, need RE-NEURONIZATION to save our lives. For God Sake what’s happening THERE? I want to walk, again, don’t you get it?
    I want to be stable, I want to venture out without dread of accident or incontinence. I want my vagus nerve to leave me the hell alone and release me from agonizing neuropathic pain. Deadened neurons desperately require focus, re-neuronization for want of a better word, improve the quality of our lives, save our lives, give us H-O-P-E.
    i want to see, again. I see fully only in my dreams. I wish to see today. Re-myelinating is, of course, essential, but is just another retarder of progression like interferon, kind of. Important, yes, even vital, yes; the essential central part of the picture, no. I’m gonna keep screaming for this. We all need to. I can exercise in therapy my pathetic and demoralizing disabled leg until its quadracep is that of Hercules’s. But, if the neurons are DEAD, what good is it? RE-NEURONIZATION, PLEASE, Our demographic is BEGGING you, whoever you are.

    • Cheryl Carvalho-Case says:

      Christopher, My daughter was diagnosed in late 2011 and has had either adverse reactions or no breaks in new and devastating lesions and atrophies in brain and spine. Please do yourself a favor and research aHSCT. If after researching, you’re still interested (I’m not in the medical field), Dr. Richard Burt is performing this in Chicago. The big IF is if you have insurance that will cover the treatment. I believe there are other doctors performing this. Sadly, the cost begins at $150,000 in the U.S., its free for some EU countries’ citizens, but costs less than a year’s supply of most DMD’s- 54,500 in Mexico (over 800 procedures with 80 favorable and no deaths directly associated with it), and about the same cost in Russia with same results.
      My daughter will be headed for Mexico (where Dr. Ruiz was honored by the Mayo Clinic and also participated in an international clinical) in September. I will gladly give you some of my research for you to read if you’re interested. If not that’s fine too. I wish you all the best and hope for your pain and disease progression to cease or at the very least abate.

      • Cheryl Carvalho-Case says:

        Sorry, I meant 80% favorable results. That means halting disease progression and even some with reversal of disabilities.

        • Chris says:

          Cheryl,

          HSCT is really only indicated for certain types of MS patients who haven’t had MS for very many years, and aren’t very advanced. Your figures are also off–HSCT is a very risky procedure with high risk of failure or serious complications from opportunistic infections. I wish you and your daughter well, but please do some more in-depth research before attempting medical procedures in other countries–also known as medical tourism. My suggestion would be to contact the FDA on their guidance about stem cell trials–none of these procedures are proven yet, they are still basically clinical trials. You might also contact other prominent doctors in the regenerative medicine field. One good place to start would be Dr Saud Sadiq at the Tisch MS center in New York City.

          • Cheryl Carvalho-Case says:

            Hi Chris,
            As I stated below, I’m familiar with Dr. Sadiq’s wonderful work with the clinical trial. That being said, the sample is too small and the FDA will hold up HSCT for additional trials and a decade to complete.
            Please read this article regarding HSCT from the American Academy of Neurology (nothing to do with medical tourism):
            http://n.neurology.org/content/90/15_Supplement/S36.004
            Specifically PLEASE read the Conclusion saying that HSCT is superior to DMDs for RRMS patients with over 2 relapses a year.
            I appreciate your input. Thank you.

        • scientist says:

          Dear Cheryl,

          HSCT is Mexico and Russia have been aggressively marketed for years in facebook dedicated page where all critical opinions are banned by paid non doctor administrators (for example Mr George Goss for Mexico). You have to know there were indeed casualties in both Mexico and Russia. Procedure is risky.
          The consensus in real science is that HSCT can be very effective for active RRMs but not for SPMS or PPMS – And risk is high – 80 % is not the result of official studies, it is more around 60 % – That is still quite impressive but not much more than Ocrevus or Tysabri for the same patients – It is better if you go to Burt because it is done in official studies and not to get as much money as possible

          • Cheryl Carvalho-Case says:

            Thank you for your reply. My daughter, diagnosed in 2011 with RRMS, has gone from 26 brain lesions (1 black hole) and 1 spinal lesion. At age 27 she now has over 100 lesions, 122 atrophied areas and several dozen spinal lesions. She is in constant pain and made this decision without my influence. Even if your 60% is accurate, those odds are better than her death from a drug or pneumonia (she is/was a teacher but can no longer be around “her precious kids.” Copaxone nearly killed her as did Rebif. Sadly we are out of options for DMDs as there is a familial history of severe adverse reactions to all kinds of medications, not just DMDs. I never said that HSCT was not without risk and there will be a very dangerous period for 4 to 6 months during and after the procedure. I would like to ask you a favor if I may? Can you please cite your 60% as opposed to 80% success rate? I’ve never read that anywhere and I read the good and the bad. Are you disputing the fact that Dr. Burt in Chicago, Dr. Ruiz in Mexico, Brazil and 2 other countries participated in the same clinical trial and had the same results? and I’ve been following Dr. Sadiq since 2011 and became very upset that his trial wasn’t updated as required by the usclinicaltrials.gov website. I came across the updates when the MS world symposium was held in Barcelona Spain from the msif site and became convinced that U.S. pharmaceutical companies and the millions they contribute to political candidates are not supportive of this for obvious reasons- that is simply my personal opinion and that of some others. I’m not against all the great things pharmaceutical companies have done to help people worldwide.
            Are you aware (not being condescending) that HSCT is being used on children with lymphoma at Tufts Floating Hospital for Children in Boston, that Nat Geo did a special segment on this in a mini series Breakthroughs and also did a positive special on the CDC that featured last resort cases that used FDA unapproved treatments (believe it was hall or door number 10, not sure)? After all I’ve read, watched, heard, and despite being scared, I have to support her decision. BTW, we have had to sell everything we owned just to barely pay the cost of treatment in Mexico. Dr. Burt in the US is three times that plus there is a year long waiting list and we have nothing left to sell and have been fundraising for months. Forgive me for being upset that only the wealthy have access to the best healthcare while other citizens are just supposed to suffer. At 63, I’m supposed to be enjoying my “golden years”, not fighting to keep my daughter alive and stopping her from suffering daily.
            All the best to you and also to anyone who suffers from this dreadful illness.

    • Chris says:

      Christopher,

      Your aggravation and desperation for a cure is understandable. There are a few things going on: First, MS is incredibly complicated… both to understand and to figure out how to modify it. Second, there is ‘hope’ in all of the DMD therapies and remyelination strategies. They aren’t a different direction than a cure, they are part of the same path to a cure. They give us all a chance by giving us more time until there is a cure, otherwise there would be nothing and no chance. Finally, if you want the whole, unadulterated truth… you can’t re-neuronize (not sure what that means) nerve fibers. Once they’re deteriorated/destroyed they’re gone, period. With remyelination it gives the CNS time to bulk up the fibers that survive, and regenerate some nerve cells and neuronal support (glial) cells. In that way you can go on to lead a fairly normal life. If you’re looking for a cure that will make you the same as you were before MS… there is no such thing. Anything coming close to that, you’re talking about 40 – 50 years in the future at least–and that includes stem cell therapies.

      There’s nothing that anyone is holding back, and no one is purposely ignoring possible cures to just focus on temporary measures. And I know because I’ve been to the labs and seen the work. Many many people are working very hard to eradicate this horrid disease. Unfortunately it’s just very complex, and takes a really long time.

  2. Al says:

    Ms. Cheryl,
    Good for you. Remember one thing, there will always be nay sayers. Stem cell replacement therapy is done everyday on people with leukemia and lymphomas, here in the U.S.A. Stem cell replacement therapy is nothing new but yes there are risks, and unfortunately the risks are numerous – some are even life threatening. But, what part of life doesn’t come with risks. Sounds to me that your daughter did her homework and everybody knows you can do your due diligence but things sometimes go sideways. No two people are exactly the same; therefore, no one treatment is going to work exactly the same on every person. Dr. Burke and the Tisch Institute, in New York, pick and choose their patient very carefully so that their research works for them. But let me say I am thankful that they are doing the research. Besides it’s shameful how much it cost to have stem cell replacement therapy done in the United States as opposed to other countries. Not to mention the cost of DMTs. I do believe that stem cell therapy is more appropriate for people with RRMS than for people with PPMS, like myself. But I have to admit I continue to look into it and I’m sitting on the fence as to whether or not to have it done. When you’re drowning you will reach for anything if you believe it’ll save your life or at least make life worth living. Please do not waste your time going back and forth with people who disagree with your daughters decision. My neurologist states that stem cell replacement therapy is not recommended for MS because MS does not kill you. I agree with my neurologist that MS does not kill but it robs your soul of everything worth living for. MS has cost me my family, friends and all I have worked for my entire life. MS may not have physically kill me but it has destroyed me. With that being said if your daughter made up her mind good for her. And God bless her that she has parents that will sacrifice everything for her. Besides the law of averages is on your side, depending on the study it’s 70 to 90% effective depending upon where you’re at on the MS spectrum. To end this simply, I would just like to say “Good Luck” to your daughter and your family.

    • Cheryl Carvalho-Case says:

      Al, a very heartfelt thank you! I’m not opposed to others’ opinions and aren’t even discouraged by them. Its always good to hear all sides before making a decision. Yes, MS does not kill by itself, it just painfully sucks the life out of some. I’ve become friends with a lady from Denver who could not walk without assistance and after HSCT wore heels and walked in them (her EDSS was 7+)!
      Please keep reading about HSCT because I’ve seen some studies where patients other than those with RRMS have had positive results. Not sure if you are aware of and read the MSIF.org site (MS International Federation), but I’ve found a lot of information there too.
      I’m still waiting for citations from “scientist”, since you and I have the same percentages. Despite the dangers involved with HSCT I’d take those odds any day.
      I truly wish that I could take away your pain and the pain of all others suffering from MS, and wish you all the best. Thank you again for your kind words of support.

  3. Christopher says:

    None of you know me, and this is not a fight or an argument. This has nothing to do with being a “nay sayer,” or any other ridiculous euphamism. The information I’m providing is based on hard science, and work I have been personally involved with in assisting researchers in regenerative medicine studies. I was trying to provide you with the best information available for what you are attempting. In some cases yes HSCT has worked, but for many it hasn’t and it is very risky. And in the case of childhood leukemia it is very effective (you mistakenly confused this as lymphoma), but cancer and multiple sclerosis are nowhere near the same in treatment. Also the effects of HSCT for MS, if it even works, are not permanent.

    I’m not saying don’t have hope… just be careful without all the facts, and you definitely don’t have all the facts. I wish you good luck.

  4. Christopher says:

    Mr. Al,

    Your figures are unfortunately way off. There is no type of therapy anywhere for MS that has a 70% – 90% success rate, and it certainly doesn’t depend on some type of spectrum. There are many factors that affect outcomes other than the MS trajectory based on the main types of designation (i.e. RRMS, SPMS, etc).

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