Chi3l3 Protein Favors Production of Myelin Repair Cells, Mouse Study Determines

Chi3l3 Protein Favors Production of Myelin Repair Cells, Mouse Study Determines

A protein marker for activated immune cells called Chi3I3 is key for the production of myelin-forming cells, and may become a target to boost myelin repair in multiple sclerosis (MS), according to a new study.

The research, “Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation,” was published in the journal Nature Communications.

MS is characterized by progressive loss and disrupted repair of myelin, a protective layer of nerve fibers formed by cells called oligodendrocytes. Because these cells are highly susceptible to injury, the differentiation of oligodendrocytes from neural stem cells (NSCs) — a process called oligodendrogenesis — is critical for repair and replenishment of the damaged myelin.

Immune cells called microglia and macrophages contribute to the proper environment for the initial steps of NSCs’ differentiation in a small stem-cell niche in the adult brain, known as subventricular zone (SVZ). Then, oligodendrocyte precursor cells migrate to the site of myelin damage and mature into oligodendrocytes.

Prior studies in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, showed that activated microglia support regeneration during the acute phase of the disease, but may have the opposite effect during chronic disease.

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Regeneration-supporting microglia produce high levels of Chi3I3, a marker for activation of microglia and macrophages. However, its function in the central nervous system (CNS) — the brain and spinal cord — remains largely unknown.

Now, a team from Charité — Universitätsmedizin Berlin, in Germany, used the EAE model to better understand the role of Chi3I3.

Results showed that expression of the mouse gene Chi3l3 increased up to 3,471-fold during peak disease, decreasing to nine-fold during chronic EAE. Chi3I3 protein was detected only during the acute phase, and was found at the same sites (co-localized) with the microglia and macrophage protein marker CD11b.

Then, genetic manipulation to lower Chi3l3 levels in microglia prior to EAE induction, accelerated disease onset and increased its severity during the chronic phase, while also reducing the generation of oligodendrocyte precursor cells. Such results are “consistent with a mechanism of Chi3l3-induced clinical recovery that involves oligodendrogenesis,” the scientists wrote.

In both mice and in human cells, the investigators observed that administration of Chi3l3 into the SVZ induced an increase in the production of oligodendrocyte precursor cells.

“We have found that the Chi3l3 protein plays a central role in the body’s capacity to produce new myelin-forming oligodendrocytes,” Sarah-Christin Starossom, the study’s first author, said in a press release.

Starossom, a researcher at the NeuroCure Cluster of Excellence and the Experimental and Clinical Research Center, added that Chi3l3 “initiates the differentiation of neural stem cells into myelin repair cells, which restore the electrical insulation around damaged nerve cells.”

The team further found that, in NSCs, Chi3l3 favored oligodendrogenesis by activating the epidermal growth factor receptor (EGFR) — previously linked with remyelination — without affecting cell proliferation, survival, or self-renewal.  This was linked to altered levels of specific proteins that regulate gene expression (called transcription factors), namely increases in Olig1Olig2 and Sox10, but decreases in Id2Id4, and Hes5.

Subsequent experiments using pharmacological inhibition, as well as genetic manipulation, revealed that the effect of Chi3I3 in oligodendrogenesis is mediated by the MAPK cellular signaling pathway.

To assess the clinical relevance of their findings, scientists analyzed the effect of the human genes CHI3L1 and CHIT1 — these genes share significant sequence similarity with Chi3l3, and are highly abundant in the CNS in relapsing-remitting MS. The results revealed that these human genes also induce oligodendrogenesis.

“We hope to use this knowledge to develop a new generation of drugs that can be used in the treatment of multiple sclerosis,” Starossom said.

“As a next step,” she added, “we will study in greater detail whether Chi3l3 or related proteins can be used to reduce the neurological symptoms of MS.”

26 comments

  1. Kerry Lewis says:

    Why does it take so long to medication s to the public stuff like this should b hurried up,some people it might b to late,this medication needs to get out fast!

  2. Pam Brity says:

    My son has a stem cell transplant in 2009 and has had no active lesions since. What he deals with now is damage to his myelin. This would be awesome!

    • Helena Botelho says:

      Dear Pam. I also had a Stem Cell transplant. I’m actually taking these vitamins called Coenzyme Q10, and Alpha Lipoic Acid. That helps by renewing New cells. I feel great with those vitamins. I hope it helps him too.

        • donna f. says:

          My new neurologist down in the city also told me to take those for the same reason. I just started in April. I’m hoping it helps. I recently started the infusion of Ocrevus, the only drug out now to help stop the progression of my type of ms. I’m hoping it helps.

  3. This is good news if it is found to work . When will it become available for clinical trails ? I am sure there would be more than enough people that volunteer to sign up for the trails . Positive news such as this gives hope for the future.

  4. Carol Trautt says:

    For over a year I’ve been taking clemastine fumarate 2.68mg at night and 500mg of taurine. Also some Red Bull. I notice that I can walk better. My doctor says my MRI’s are stable.

    • Audrey Rosner says:

      I read about how helpful taurine is for brain cells. The latest edition of Life Extension Magazine has a good article.

  5. Sheri C says:

    I’ve had MS for over 17 years and have kept it at bay with Low Dose Naltrexone and DIM and a high quality Omega lll. There are ways to build the myelin with diet as well. Anything that promotes the support of the Mitochondria. Meaning …. tons of organic vegetables raw, juiced and very lightly steamed. Also eliminating wheat, saturated fats, sugar, bad carbs cows milk. It’s not easy but can be done. LDN needs to be prescribed and compounded by a special pharmacy. Not everyone will prescribe because they don’t even know of this use for it. They finally started using it at OHSU in the MS clinic so it finally is being recognized by some more open minded clinicians.
    There was a study done at Penn Medical University in 2015 showing that a high viral load of the herpes virus specifically Epstein Barr, and HHV6 and CMV can cross the blood brain barrier and cause brain lesions mimicking MS and other brain disorders. My test were 500 times a normal load for EB and HHV6 so I’m being treated for the viruses with an anti virals, Valtrex and Femvir for 3-4 months each year. Pretty nasty meds and not pleasant to live on at least for me, but at this point I’ll try anything.
    I am NOT a doctor or nurse or anything in the medical field these statement are only from my personal experience and from many years of reading and studying and experimenting on myself.
    I am not in a wheelchair, I am not showing any signs of MS and I am 61 years old. I hope this is helpful to anyone with MS.
    SLC

  6. Pat says:

    I hope this discovery can be applied to those with CMT (Charcot- Marie- Tooth disorder), another disease that destroys the myelin sheath around nerves. CMT is a genetic disease and it’s all throughout my family. It’s cruel like MS.

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