Stem Cells Make New Myelin, Show Potential for AD

As scientists celebrate the 2012 Nobel Prize in Physiology or Medicine for the development of induced pluripotent cells, researchers are looking to traditional and modern stem cell sources to treat diseases of the brain in both young and aging people. An old standby, fetal brain cells, provides a potential treatment for a missing myelin disorder, according to two papers in the October 10 Science Translational Medicine. The authors treated four children, in addition to mouse models, with neural stem cells banked by StemCells, Inc., of Newark, California. The treatment was safe, and the team saw evidence that the transplants morphed into the needed oligodendrocytes that myelinate naked axons.

Another potential source of stem cells treatments is the body’s own cells. In the September PLoS One, researchers from Seoul National University describe how they transplanted easily obtained adipose-derived stem cells into Alzheimer’s model mice, and achieved an improvement in learning and memory. Senior author Yoo-Hun Suh believes the transplanted stem cells provided cytokines and growth factors that eliminated amyloid-β and supported sickly neurons.

It’s in the Bank
StemCells, Inc., maintains a collection of neural stem cells (NSCs) expanded and frozen from a donated fetal brain (Uchida et al., 2000). Researchers are testing this cell population in a variety of conditions, such as macular degeneration, spinal cord injury and Batten disease, a rare childhood neurodegenerative disorder. The clinical trial is the first human safety study with these cells to be published, said senior author David Rowitch of the University of California, San Francisco.

Rowitch, first author Nalin Gupta, and colleagues injected the NSCs into four young boys with a rare disorder called Pelizaeous-Merzbacher disease, or PMD. Affecting one in 200,000-500,000 children, this extremely rare condition is one of many leukodystrophies. These diseases damage the heavily myelinated white matter of the brain. PMD results from a recessive mutation in the gene for proteolipid protein 1 (PLP1), a key myelin component. Children with PMD often require machines to breathe and eat, and many cannot sit up, crawl, walk or talk, Rowitch said. Those with the severest disease will die from it.

Animal studies showed that StemCells’ banked NSCs happen to be particularly good at turning into oligodendrocytes, making PMD an ideal test case. Plus, since the kids make almost no myelin, their brains would provide minimal background signal in a magnetic resonance image (MRI) for myelin. Any evidence of myelination would have to come from the transplanted cells.

Gupta injected three million NSCs into each boy, dividing the cells between four shallow sites in the frontal lobe. Over the next year, the researchers examined the children and performed MRIs. “We saw signals that are suggestive of myelin production,” Rowitch said of the images. (They did not want to subject the children to a biopsy to confirm it.)

Three of the boys improved in skills such as walking and eating on their own. However, this was probably not due to the injection of the small stem cell populations at a few sites, Rowitch said, but merely their natural development. In this Phase I safety study, all the researchers were aiming for is that the cells should do no harm, which they did not. The team will continue to follow the participants for four more years, and Rowitch is pondering the design for a controlled, Phase II trial to look for benefit from the treatment.

Gupta’s work depended on a preclinical mouse study, performed before the trial but published alongside it in Science Translational Medicine. Researchers at StemCells, Inc., led by first author Nobuko Uchida, grafted NSCs from the bank into the corpus callosum, fornix, and cerebellum of young shiverer mice. Lacking the gene for myelin basic protein, these mice and are a good phenocopy of human PMD, said senior author Stephen Back of the Oregon Health & Science University in Portland, where most of the animal analysis was performed.

The researchers implanted newborn and three-week-old mice. The latter had begun to suffer tremors because their oligodendrocytes encircled their axons with loosely wound, dysfunctional myelin. No matter the age, the NSCs found their niche. Sixty to 70 percent differentiated into oligodendrocytes, migrated past the injection site, and produced myelin sheaths with normal gaps, or nodes of Ranvier, along the axons. Electrophysiology on brain slices indicated that neural transmission sped up due to the new myelin. “They form nice oligodendrocytes,” said James Weimann of Stanford Medical School in Palo Alto, California, who was not involved with the study (see full comment below). “The interspacing of the nodes looks great, as does the conduction velocity.”

Weimann was pleased to see that five to seven percent of the transplanted NSCs expressed the cell proliferation marker Ki67. This indicated the cells were dividing and keeping up a good-sized pool of progenitor cells. But they did not proliferate so much as to form tumors, which bodes well for long-term treatment. The team could not measure transplant half life, since shiverer mice are quite ill, and they died within 10 weeks. However, in other experiments, transplanted oligodendrocyte progenitors have persisted for more than a year (Windrem et al., 2008).

The key challenge in translating these results to people, Weismann suggested, will be encouraging the new cells to migrate and populate the brain. While human transplants travel well in mouse brains, it is not known if they will do the same in human brains.

If the researchers are successful, people with PMD could be the first of many to benefit from their efforts. “This raises the possibility that stem cell therapy may be part of the tools we use to repair or slow injury to the white matter,” Back said. “The challenge is to fine-tune the therapy to the unique characteristics of [each] particular disease.” In children, cerebral palsy might be a possible target, he suggested. People with demyelinating conditions such as multiple sclerosis and vascular dementia might also benefit—but it could take decades to reach that point, Rowitch noted.

Auto-Harvest
In the PLoS One paper, the Korean team focused not on the white matter but on the grey, in the hopes of designing a treatment for Alzheimer’s. They used a different source, namely human stem cells from people undergoing liposuction. Obtaining these adipocyte-derived cells is “very simple and convenient,” said study author Suh. He envisions someday transplanting a person’s own fat-derived cells into the brain, thus eliminating the possibility of immune rejection. Plus, he noted, using one’s own cells is more ethically palatable than cells from donated fetal tissue. Scientists have tested adipose-derived stem cells in models of Huntington’s disease (Lee et al., 2009) and stroke (Bhang et al., 2009).

Joint first authors Saeromi Kim and Keun-A Chang used the stem cells to treat Tg2576 mice expressing mutated human amyloid precursor protein. They injected the stem cells intravenously in one set of mice, and intracranially in another. In a water maze test, both sets of treated animals matched wild-type mice in recalling the place where a hidden platform used to be. “Learning and memory almost recovered to normal,” Suh said.

The researchers counted fewer amyloid plaques, and measured less amyloid-β overall, in the brains of transplanted animals. Suh believes the benefits stem from the upregulation of the anti-inflammatory cytokine IL-10, and neurotrophic growth factors such as VEGF, that the researchers saw in the brains of treated animals. The team noticed no negative side effects. Suh is planning a clinical trial.

“Adipocytes are a great resource for stem cell collection,” commented Tsuneya Ikezu of Boston University, who was not involved in the study (see full comment below). At the same time, he expressed some reservations about the preclinical data. He was not convinced that the stem cells actually crossed from the circulatory system into the brain. Suh, in an email to Alzforum, responded that the stem cells and neurons must be in direct contact to promote symptom improvement he observed. In addition, Ikezu suggested that the beneficial molecules such as IL-10 could have arisen due to a peripheral immune response to the foreign human cells, not because of the cells’ protective activity. Suh believes the mice did not mount an immune response to the human cells, because the anti-inflammatory cytokine IL-1β was actually decreased in the animals.

While transplants appear to be a simple way to provide new stem cells where they are needed, another option is to keep the whole treatment process inside the body. Transdifferentiation, as it is called, shepherds cells from one differentiated fate to another, skipping the Nobel prize-winning step of induced pluripotency (reviewed in Vierbuchen and Wernig, 2011). Researchers at the Ludwig-Maximilians University in Munich, Germany, recently reported that they reprogrammed human pericytes directly into neurons. They obtained the pericytes from tissue samples donated by people who had brain surgery to remove a lesion or treat epilepsy. “Our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons,” the authors concluded (Karow et al., 2012).

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