Human embryonic stem cells rescue mice from fatal brain disease

Researchers report today that human stem cells can rescue mice from an otherwise fatal neurological condition caused by the brain's inability to conduct nervous impulses. The findings, published in the journal Cell Stem Cell, raise the possibility of cell transplantation treatments for a number of neurological diseases in which the ability of nerve cells to communicate with each other has been compromised.

The new study, led by Steven Goldman, a professor of neurology and neurosurgery at the University of Rochester Medical Center, used glial progenitor cells (GPCs) obtained from the brains of human fetuses that were aborted between 19-22 weeks of gestation. Normally, these cells differentiate to produce oligodendrocytes, which produce the myelin that ensheaths axons in the central nervous system.

Myelin is a complex substance consisting of fatty lipids and proteins, which increases the velocity at which they conduct nervous impulses. An individual oligodendrocyte - the name means "cell with few branches" - straddles a bundle of nerve fibres, and has up to 50 broad, flat processes, each of which extends to a different axon, and wraps itself around an approximately 1mm-long segment of it.

An axon in the central nervous system is therefore ensheathed by many small lengths of myelin, each originating from a different oligodendrocyte. The myelin segments are interspersed by small, unmyelinated regions known as Nodes of Ranvier. A nervous impulse generated in a myelinated axon can be propagated much more quickly than one in an unmyelinated axon, because it can jump from one node to the next, in a process called saltatory conduction.

When the integrity of the myelin sheath is compromised in humans, the results can be extremely debilitating. The most common demyelinating disease is multiple sclerosis, in which widespread loss of myelin in the brain can lead to muscle spasms, visual defects, and cognitive and emotional impairments. Other conditions in which there is a loss of myelin include cerebral palsy, spinal cord injury and the leukodystrophies. 

Goldman and his colleagues transplanted the fetal GPCs into the brains of shiverer mutant mice, which carry a mutation that results in an inability to produce myelin. These mice exhibit severe neurological defects - they have seizures, are unable to walk, and usually die at 18-21 weeks of age, because they cannot feed.

Fine glass pipettes were used to insert the stem cells directly into the skulls of 26 newborn shiverer mice. Each animal received about 300,000 donor cells, dispersed over four locations in the cerebral cortex, and a fifth in the cerebellum. As a control, 29 mice were treated with a placebo, and 59 were left untreated.

Some of the mice treated with GPCs survived for longer than the untreated animals. All of the controls, and most of the experimental animals, died by 150 days of age. However, 6 out of the 26 experimental animals remained alive beyond more than 150 days, and 4 of them were still alive a year after receiving their treatment.

The mice that survived exhibited significant neurological improvements. Although all the animals deteriorated identically over the first few months after birth, the experimental animals surviving beyond 150 days displayed reduced numbers of seizures, and their movements improved incrementally, such that, by 35 weeks of age, they appeared normal.

Analysis of the experimental animals' brains showed that the GPCs spread widely throughout both the brain and spinal cord following transplantation. The mice exhibited essentially complete myelination which was indistinguishable from wild-type (healthy) animals. Furthermore, the organization of the Nodes of Ranvier appeared normal, and electrophysiological recordings showed that the conduction velocity of axons in the corpus callosum was comparable to wild-types.

The findings raise hopes of treatments for demyelinating, but they come with several caveats which make it unlikely that they will be applicable to humans any time soon. For example, it is unclear why only a minority of the mice treated with the stem cells survived. Also, the mice used in the study carried a second mutation, which suppressed their immune response to the transplanted cells. Any treatment developed might therefore require patients to be given immunsuppressant drugs prior to implantation of the cells, and this carries the risk of infection. 

Related:

• Time-lapse movies of oligodendrocyte precursor migration
  

Windrem, M.S., et al. (2008). Neonatal Chimerization with Human Glial Progenitor Cells Can Both Remyelinate and Rescue the Otherwise Lethally Hypomyelinated Shiverer Mouse. Cell Stem Cell, 2: 553-565. [Full text]