Stem Cells May Boost Myelin Production in CMT1A, Study Suggests
Mesenchymal stem cells (MSCs) can boost myelin-producing cells and the function of peripheral nerves — which supply movement and sensation to the arms and legs — in a mouse model of Charcot-Marie-Tooth type 1A, a study shows.
The therapeutic benefits of MSCs, which can give rise to many other cell types, are mediated by the release of certain cytokines, molecules that mediate and regulate immune and inflammatory processes.
The study, “Cytokines secreted by mesenchymal stem cells reduce demyelination in an animal model of Charcot-Marie-Tooth disease,” was published in the journal Biochemical and Biophysical Research Communications.
Mutations that cause a duplication in the PMP22 gene’s DNA sequence are the main cause of CMT1A, the most common subtype of CMT type 1. This gene codes for the PMP22 protein, which is a key component of the myelin sheath that coats nerve cells and ensures proper communication between them. Myelin, a fatty layer, is formed by a type of cells called Schwann cells in peripheral nerves.
An abnormal production of the PMP22 protein not only affects the structure of myelin, but also triggers the death of Schwann cells.
MSCs are gaining increasing interest as a potential therapeutic approach for a number of conditions, including neurological diseases. Present in diverse tissues, such as the umbilical cord, the bone marrow, and fat tissue, MSCs have anti-inflammatory, neuroprotective, and regenerative properties.
Now, researchers in South Korea investigated the therapeutic potential of MSCs in reducing the effect of the death of Schwann cells that produce abnormally high PMP22 protein levels.
The team incubated rat PMP22-expressing Schwann cells with human Wharton’s jelly derived-MSCs for 24 hours. Of note, Wharton’s jelly is the connective tissue surrounding the two arteries and one vein of the umbilical cord.
They then assessed the percentage of live cells. First, the investigators confirmed that compared with control Schwann cells, those with excessive PMP22 had a lower mean percentage of live cells, specifically, 84.3% vs. 91.7%.
However, when grown together with MSCs, the viability of PMP22-overexpressing Schwann cells increased to 88%. In parallel, the rate of cells undergoing apoptosis — programmed cell death, as opposed to death caused by injury — was lessened when growing MSCs with Schwann cells overproducing PMP22. That rate dropped from 7.7% to 6.0%.
Next, the scientists assessed whether MSCs also could boost the production of myelin. To answer this, they assessed the process, called gene expression, that leads to two proteins, Oct6 and MPZ. Oct6 is implicated in myelin formation and MPZ is a component of myelin.
The analysis showed that, indeed, the messenger RNA levels — the molecule generated from DNA that serves as a template for protein production — of both genes were significantly increased in PMP22-overexpressing cells grown together with MSCs.
Specifically, the mRNA of Oct6 increased by 3.7 times, while that of MPZ was 1.7 times higher.
These findings suggest that mesenchymal stem cells may protect “against the adverse effects of PMP22 overexpression and promote myelin gene expression, which might improve the symptoms of demyelinating CMT,” the researchers wrote.
In further experiments, the team showed that the therapeutic benefits of MSCs may be linked with their anti-inflammatory properties. The MSCs grown with PMP22-overexpressing Schwann cells released high levels of two cytokines, called growth differentiation factor-15 (GDF-15) and amphiregulin (AREG), they found.
GDF-15 induced a significant increase in the proportion of live PMP22-overexpressing Schwann cells compared with untreated cells (a mean of 81.1% vs. 76.5%). Moreover, GDF-15 decreased the proportion of cells undergoing apoptosis, from 10.5% to 6.3%.
Also, in PMP22-overproducing Schwann cells, GDF-15 increased the activity of the genes coding for Oct6 and MPZ.
Since all these findings were from lab (in vitro) tests, the researchers then investigated the therapeutic effects of AREG and GDF-15 in a mouse model of CMT1A.
The animals received an intramuscular injection of either cytokine, for a total of eight injections, given every other day.
Compared with control animals, those given either cytokine showed a significant increase in motor nerve conduction velocity, which reflects how fast an electrical impulse moves through nerves and is a sign of nerve function. The cytokines also boosted myelination in the sciatic nerve, a large nerve extending from the spinal cord through the legs.
Overall, these findings support the therapeutic benefits of MSCs in CMT1A, specifically via secretion of AREG and GDF-15, in lessening the loss of myelin-producing cells and boosting myelin production in peripheral nerves.
“Further elucidation of the underlying mechanisms of GDF-15 and AREG in myelination might provide a robust basis for the development of effective therapies against demyelinating CMT,” the researchers concluded.