Stem cell transplant shows promise for spinal cord repair

For the first time, Yale scientists have transplanted stem cells from an adult primate brain to repair the insulating sheath surrounding spinal cord axons in the same animal. These results, reported at the annual meeting of the Society for Neuroscience in November, raise hopes that patients’ own stem cells might one day be used to help them recover from spinal cord injuries or multiple sclerosis.

For the experiment, which was directed by Jeffery D. Kocsis, Ph.D., professor of neurology and neurobiology, a small quantity of cells was removed from the subventrical zone in the frontal lobe. The neural precursor, or stem, cells were then cloned and expanded in the laboratory before being transplanted into a region of the spinal cord from which myelin, the protective coating around the nerve fibers that increases impulse conduction speed, had been removed. The stem cells formed new myelin to cover the nerve cells.

The use of a subject’s own stem cells could circumvent the ethical and practical issues surrounding the use of fetal tissue, from which stem cells can readily be derived, and the problems associated with immune suppression that arise when transplanting foreign tissue. In the January issue of Experimental Neurology the investigators further reported that similar cells derived from the adult human brain can repair axons in a rodent model of demyelination and improve impulse conduction.

“The concept is not ready for application in patients, but the fact that it can be achieved in a primate and that the stem cells can be developed from adult human brain is significant. There’s a lot of excitement here about the potential of putting cells to work to repair the injured nervous system,” said Kocsis. But, he warned, “There are so many cell types and so many safety issues. This is the very first step in a long process for developing new clinical treatments.”

Antidepressants shown to promote new cell growth in the hippocampus

Continued use of antidepressants leads to new cell growth in an area of the brain known to suffer cell death and atrophy as a result of depression and stress, a study by Yale researchers shows.

Chronic administration of antidepressants increases the number of neurons in the adult hippocampus, which could help explain how antidepressants produce their therapeutic response, according to Ronald S. Duman, Ph.D., professor of psychiatry and pharmacology. Duman was senior author of the study, published Dec. 15 in The Journal of Neuroscience.

The hippocampus is the part of the limbic brain that is involved in learning, memory, mood and emotion. It is one of only a few regions of the adult brain where production of neurons occurs in animals, including humans. Previous studies have demonstrated that stressful experiences, both physical and psychological, lead to neuronal loss in the hippocampus and that antidepressants can block this cell loss.

Duman’s laboratory has been studying the mechanism of action of antidepressants in rodents for over 15 years. The researchers have focused on cellular actions of antidepressants, looking at the role of the intracellular signal transduction pathways that control neuronal function. They have identified several actions of antidepressants that indicate that they influence the survival or the number of neurons in the hippocampus.

This study was intended to look at whether antidepressants increased the birth of neurons in the hippocampus. The researchers tested several different classes of antidepressant drugs, as well as electroconvulsive seizure therapy (ECS) and an antipsychotic medication.

ECS is clinically the most effective treatment for cases of depression that are resistant to available drug treatments. As expected, repeated administration of ECS increased the number of neurons in the hippocampus of the brain by 50 percent. The chemical antidepressants tested increased the number of neurons in the same area by 20 percent to 40 percent. The antidepressants that were administered included a monoamine oxidase inhibitor (tranylcypromine), a serotonin-selective reuptake inhibitor (fluoxetine) and a norepinephrine-selective reuptake inhibitor (reboxetine).

Acute administration of the antidepressants (one to five days) did not lead to any significant cell change. Results were seen after 14 to 28 days of administration, which is consistent with treatment regimens for the therapeutic response to antidepressants. These studies suggest that increased neuro-genesis in the hippocampus could counter the effects of stress on hippocampal atrophy and contribute to the actions of antidepressant treatments.

Probing the genetic basis of emphysema

In separate studies, Yale researchers have demonstrated that the genes that code for interleuken-13 (IL-13) and gamma-interferon cause pulmonary emphysema.

Using transgenic mice that were genetically engineered to express these genes in the adult mouse lung, Jack A. Elias, M.D., section chief of pulmonary and critical care medicine, and a team of researchers including Zhou Zhu, M.D., Ph.D.; Tao Zheng, M.D.; Chun Guen Lee, M.D.; Bing Ma, M.S.; and Qingsheng Chen, M.D., have demonstrated that these genes, which are known to cause inflammation, also cause pulmonary emphysema similar to the kind seen in patients with chronic obstructive pulmonary disease (COPD). COPD affects 16 million people in the United States alone and is the fourth leading cause of death worldwide.

The first study, published in the November issue of The Journal of Clinical Investigation, highlighted the potential importance of IL-13 in the development of emphysema and in the exaggerated mucus production seen in these disorders. Since IL-13 is also thought to contribute to asthma, this study also demonstrated that common mechanisms might underlie the development of both of these lung disorders.

The second study, published in the December issue of The Journal of Experimental Medicine, shed light on the potential role of gamma-interferon in the development of COPD. Elias notes that the symptoms in the two transgenic systems used in the studies can vary from one person to another.

“We saw different types of inflammation, differences in mucus production and different rates of emphysema development in the two different transgenic systems,” said Elias. “These differences recapitulate, in many ways, the individual-to-individual differences seen in groups of patients with COPD and may explain why only some patients have exaggerated mucus production while others have rapidly progressive or slowly progressive disease.”

Elias adds, “The results also provide a mechanistic explanation for the observation that asthmatics who smoke cigarettes have the most rapid rates of loss of lung function.”

In the normal lung, there is a fine balance between proteins that degrade lung tissue, called proteases, and proteins that inhibit protease function, called antiproteases. Researchers have assumed that emphysema develops when the activity of the proteases overwhelms the controlling capacity of the antiproteases.

“Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. However, the way that inflammation causes emphysema has not been defined until now,” said Elias. “Our studies demonstrate that IL-13 and gamma-interferon, gene products that regulate inflammation, can also trigger emphysema.” The studies also demonstrated that IL-13 and gamma-interferon caused impressive increases in two classes of proteases called matrix metalloproteinases and cathepsins. They also caused selective decreases in antiproteases.

Estrogen deprivation associated with loss of dopamine cells

Estrogen deprivation leads to the death of dopamine cells in the brain, a finding by Yale scientists that could help explain why Parkinson’s disease is more likely to develop in men than in premenopausal women and why it increases in women after menopause.

“Without estrogen, more than 30 percent of all the dopamine neurons disappeared in a major area of the brain that produces the neurotransmitter dopamine,” said D. Eugene Redmond Jr., M.D., professor of psychiatry and neurosurgery and director of the Neural Transplantation and Regeneration Program.

The discovery was made after a team led by Redmond removed the ovaries of female monkeys, thereby depleting their bodies of estrogen and other gonadal hormones. Within 10 days, key neurons in the brain that protect against Parkinson’s disappeared. After 30 days the cells appeared to be permanently lost. The scientists were able to regenerate the cells by administering estrogen within 10 days.

Redmond said monkeys were used in the study because they have menstrual cycles and many other close similarities to humans. The researchers were interested in sexual differences in dopamine neurons in the substantia nigra area of the midbrain, whose destruction is associated with Parkinson’s disease and dementia.

The study was published in the December issue of The Journal of Neuroscience. The principal investigator was Csaba Leranth, M.D., Ph.D., professor of obstetrics and gynecology and of neurobiology.

Also in Findings:

Stem cells and spinal cords  |  Antidepressants promote cell growth  |  Emphysema genes  |  A link between estrogen and dopamine

Chronicle  |  Rounds  |  Et cetera    

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Originally published in Yale Medicine, Spring 2001.
Copyright © 2001 Yale University School of Medicine. All rights reserved.