Stem cells against multiple sclerosis

Human stem cells restored myelin sheaths in the brains of adult mice

Alice Bakhareva, N+1

Glia progenitor cells, which were transplanted into the demyelinated brain of adult mice, spread throughout the forebrain, differentiated into oligodendrocytes and restored the myelin sheaths of axons. As a result, motor functions and electrophysiological parameters of nerve fibers improved in animals.

Article by Windrem et al. Human Glial Progenitor Cells Effectively Remyelinate the Demyelinated Adult Brain is published in the journal Cell Reports.

Violation of the myelin sheaths of neurons leads to a number of neurodegenerative diseases, including multiple sclerosis, and contributes to some mental disorders. Scientists propose to compensate for demyelination by transplanting the precursors of glial cells of oligodendrocytes, which form myelin sheaths in the central nervous system.

It has already been successfully transplanted human oligodendrocyte precursors into newborn mice with mutations in the gene of the main myelin protein (MBM). In such animals, the formation of myelin sheaths is disrupted, tremor (trembling) develops shortly after birth, and the animals die at the age of several months. Transplantation of oligodendrocytes restored myelination and prolonged the life of mice. However, scientists have not yet investigated whether the precursors of glial cells can settle in the adult brain and myelinate it.

A group of researchers from the University of Rochester Medical Center led by Steven Goldman transplanted glial cell precursors into adult mice with mutations in the MBM gene, as well as animals in which demyelination was artificially induced using cuprizon. Stem cells were injected into the corpus callosum of mice aged four to six weeks (eight "trembling" mice and 14 control mice). 12-15 weeks after surgery, the brain was extracted and the distribution of donor cells, differentiation of oligodendroites and myelination of neurons were evaluated.

The transplanted glia precursors successfully spread throughout the forebrain of mice and caused the active formation of myelin sheaths. These cells expressed genes that are associated with differentiation into oligodendrocytes, cell movement, and the onset of myelination.

Myelinated fibers (green) and human cells (red) in the corpus callosum of a mouse 13 weeks after surgery. Drawings from the article by Windrem et al.

Then the stem cells were transplanted into newborn wild-type mice (without mutations in the MBM gene), and at the age of four months they began to feed cuprizon. After the termination of the cuprizon diet, human precursors of glial cells began to actively spread through the brain, differentiate and restore the myelin sheaths of neurons. This means that transplanted stem cells can remyelinate not only axons that have never had membranes, but also processes that have lost myelin in adulthood.

A: experiment design. After birth, the mice are transplanted with human glial cell precursors, and from 17 to 29 weeks, the animals are fed cuprizon. B, C: the spread of human cells in the brain of mice (B: control; C: who consumed cuprizon) at 49 weeks from birth.

In the third experiment, adult mice were fed cuprizon for 20 weeks, and only four weeks after the start of the diet, during active demyelination, glial cell precursors were transplanted. The myelin–free environment stimulated stem cells to actively disperse and differentiate into oligodendrocytes - 36 weeks after surgery, more than a quarter of the oligodendrocytes in the brains of mice were human.

Design of the third experiment. Mice are transplanted human stem cells at 10 weeks after birth, and cuprizon is fed from the sixth to 26 weeks.

Finally, the scientists assessed the physiological improvements in the condition of "trembling" mice after stem cell transplantation. The animals were tested on a treadmill, the conductive ability of the fibers of the corpus callosum and the degree of their myelination were measured. 

Seven out of eight operated animals remained on the track for five seconds after 18 weeks; among control mice, only two out of eight coped with the test (p<0.05). In the nerve impulses of the fibers of the corpus callosum, the component corresponding to thick myelinated fibers increased, and, as a result, the pulse conduction rate increased (p=0.02). The electron and confocal microscope images show that the glial precursors differentiated and oligodendrocytes formed myelin sheaths on axons.

Electron micrographs of axons in cross section. On the left is a control animal without myelin sheaths, on the right is an axon with myelin.

Scientists are experimenting with transplanting a variety of stem cells: for example, with the help of testicular cells, it was possible to restore the fertility of mice. However, there are also unsuccessful examples: thus, stem cell transplantation from old animals worsens the condition of recipients, regardless of their age.

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