Umbilical Cord Blood Stem Cells Revive Child From Persistent Vegetative State

Physicians from Ruhr-Universitaet-Bochum (RUB) have successfully treated cerebral palsy in a 2.5-year old boy with his own cord blood.

“Our findings, along with those from a Korean study, dispel the long-held doubts about the effectiveness of the new therapy,” says Dr. Arne Jensen of the Campus Clinic gynaecology. Jensen collaborated with his colleague Prof. Dr. Eckard Hamelmann of the Department of Pediatrics at the Catholic Hospital Bochum (University Clinic of the RUB). This case study was published in the journal Case Reports in Transplantation.

At the end of November 2008, a young child’s heart stopped (cardiac arrest), and his brain suffered oxygen deprivation, and, consequently, severe brain damage. He was in a persistent vegetative state, and his body was completely paralyzed. This condition, infantile cerebral palsy, until now, has no recognized treatment. Typically, the prognosis of children with infantile cerebral palsy is rather grim, since the chances of survival miniscule and months after suffering severe brain damage, the surviving children usually only exhibit minimal signs of consciousness. According to the physicians at RUB, “The prognosis for the little patient was threatening if not hopeless.”

However, this child’s persistent parents scoured the literature for alternative therapies to infantile cerebral palsy. Arne Jensen explains. “They contacted us and asked about the possibilities of using their son’s cord blood, frozen at his birth.”

Nine weeks after suffering brain damage, on 27 January 2009, Jensen and his colleagues administered the child’s prepared cord blood intravenously. They studied the child’s progressive recovery at 2, 5, 12, 24, 30, and 40 months after treatment.

After the cord blood therapy, the patient, however, recovered quickly. Within two months, the child’s spasms decreased significantly. He was able to see, sit, smile, and to speak simple words again. Forty months after treatment, the child was able to eat independently, walk with assistance, and form four-word sentences. “Of course, on the basis of these results, we cannot clearly say what the cause of the recovery is,” Jensen says. “It is, however, very difficult to explain these remarkable effects by purely symptomatic treatment during active rehabilitation.”

Just listen to the description of the child’s recovery from this paper:

After two years, there was independent eating and speech competence of eight words (pronunciation slurred, mimicking prosody) with broad understanding. The patient moved from a prone to a free sitting position and crawled without cross-pattern, but using the arms. Independent passive standing, walking with support, and independent locomotion in a gait trainer was possible (video S5). He played imaginative games, and recognized colours, animals, and objects, assigning them correctly. Fine motor control improved to such an extent that he managed to steer a remote control car (video S6). At 30 months, he formed two-word-sentences using 80 words.

After 40 months, there was further improvement in both receptive and expressive speech competence (four-word-sentences, 200 words), walking (Crocodile Retrowalker), crawling with cross-pattern, and getting into vertical position.

And this is from a child who was a in a persistent vegetative state, who could neither speak, nor eat on his own, nor talk.

In animal studies, scientists have examined the therapeutic potential of cord blood. In a previous study with rats, RUB researchers revealed that cord blood cells migrate to the damaged area of the brain in large numbers within 24 hours of administration.  Umbilical cord stem cells are also known to secrete gobs of neurotropic molecules that stimulate neuron growth and differentiation, promote neuron survival, quell inflammation, staunch star formation in the brain (gliosis), and stimulate the growth and formation of blood vessels.

In March 2013, in a controlled study of one hundred children, Korean doctors reported for the first time that they had successfully treated cerebral palsy with someone else’s cord blood.

These results show that cord blood has tremendous therapeutic potential for pediatric neurological conditions.  This remarkable recovery is seemingly miraculous.  Certainly this merits more work and excitement.


Human Brain Cells Made in the Lab that Grow in the Mouse Brain

The laboratory of Arnold Kriegstein, who serves as the director of the Broad Center of Regenerative Medicine and Stem Cell Research at UC San Francisco has made a vitally important type of brain cell from human pluripotent stem cells that smoothly integrates into the brains of laboratory animals. Such a discovery could potentially provide cells that could treat epileptics, Parkinson’s disease or even Alzheimer’s disease.

Medial ganglionic eminence (MGE) cells are a unique type of progenitor cell in the developing brain that guides cell and axon migration. The MGE is located between the thalamus and the caudate nucleus in the developing brain and it facilitates tangential cell migration during embryonic development in the brain.

In the developing brain, cells move radially, along special glial cells that act as tracts for the migrating cells, or tangentially between the radial glial cells. Those cells that move tangentially (perpendicular to the radial glial cells) are specially designated to form GABAminergic neurons; that is neurons that use gamma-amino-butyric acid as their neurotransmitter. However, the MGE also contributes cells to the basal ganglia, which helps control voluntary movement, and guides those axons that grow from the thalamus into the cerebral cortex, or, conversely, those axons that grow from the cerebral cortex to the thalamus. The MGE is a transient structure, and after one year of age, the MGE disappears.

medial ganglionic eminence

Making MGE cells from pluripotent stem cells has been one of the holy grails of developmental neurobiology. Now Kirgstein’s laboratory has succeeded in doing just that.   By subjecting human embryonic stem cells and induced pluripotent stem cells to a complex and extensive differentiation procedure, Kirgstein and his coworkers succeeded in producing large quantities of MGE progenitors that readily matured into forebrain interneurons.  They treated pluripotent stem cells with several growth factors, but more importantly, they timed the delivery of these factors to shape their developmental path.  By conducting neurophysiological experiments on the cells as they differentiated them, Kirgstein and coworkers discovered that they could effectively determine if they had properly derived GABAminergic interneurons.  Jiadong Chen in Kirgsteins’s laboratory showed that the MGE-like progenitors formed proper synapses or connections with other neurons and responded appropriately when stimulated.  Also, as the interneurons matured into more adult-like interneurons, their neurophysiology became more adult-like.  

When grown in the laboratory in culture or when injected into the brains of mice, these MGE-like cells developed into GABAergic interneuron subtypes that displayed the properties of mature GABAminergic neurons.  Also, the cells kept these properties for up to 7 months, and therefore, faithfully mimicked endogenous human neural development.

When injected into mouse brains, the MGE-like progenitors integrated into the brain and formed connections with existing cells.  According to Kirgstein, this property of these cells and their behavior in living tissue makes them prime candidates to test interneuron malfunction that is characteristic of human diseases.  They might also provide material to treat patients who suffer from neurological diseases that affect interneuron function.

According to Kirgstein, “We think that this one type of cell may be useful in treating several types of neurodevelopmental and neurodegenerative disorders in a targeted way.”

In earlier work, Kirgstein implanted mouse MGE cells into the spinal cord of mice that suffered from neuropathic pain.  The implanted cells reduced the pain of those mice, suggesting that they can be used to treat other neurological conditions such a spasticity, Parkinson’s disease and epilepsy.

The first author of this paper, Cory Nicholas said, “The hope is that we can deliver these cells to various places within the nervous system that have been overactive and that they will functionally integrate and provide regulated inhibition.”

Neural Cells Made from Monkey Skin Cells Integrate into Monkey Brains and Form Neurons

Stem cell scientists from the University of Wisconsin at Madison have transplanted neural cells that were made from a monkey’s skin cells into the brain of that same monkey. The transplanted cells formed variety of new brain cells that were entirely normal after six months.

This experiment is a proof-of-principle investigation that shows that personalized medicine in which regenerative treatments are designed for specific individuals is possible. These neural cells were derived from the monkey’s skin cells and were, therefore, no foreign. Therefore, there is no risk of them being rejected by the host immune system.

Su-Chun Zhang, professor of neuroscience at the University of Wisconsin-Madison, said: “When you look at the brain, you cannot tell that it is a graft. Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope.”

Marina Emborg, associate professor of medical physics at UW-Madison and one of the lead co-authors of the study, said: “This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well-integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part.”

The skin-derived neural cells were implanted into the monkey brain by means of a state-of-the-art surgical procedure whereby the surgeon was guided by a live MRI. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had brain lesions that caused Parkinson’s disease. Up to one million Americans suffer from Parkinson’s disease, and some 60,000 new patients are diagnosed with it each year. Parkinson’s disease results from the death of midbrain neurons that manufacture the neurotransmitter dopamine.

The cells that were transplanted into the brain were derived from induced pluripotent stem cells (iPSCs), which, like embryonic stem cells, can develop into virtually any cell in the adult human body.

Once the iPSC lines were established, Zhang and his colleagues differentiated them into neural progenitor cells (NPCs), which have the ability to form a wide variety of brain-specific cells. Zhang was the first scientist to ever successfully differentiate iPSCs into NPCs, and therefore, this paper utilized his unique expertise.

According to Zhang, “We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells. By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine. Now we want to more ahead and see if this leads to a real treatment for this awful disease.”

Another positive sign was the absence of any signs of cancer, which is a troubling but potential outcome of stem cell transplants. Zhang jubilantly but guardedly announced that the appearance of the cells is “normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that. And when you look at what the cells have become, the become neurons with long axons, as we’d expect. The also build oligodendrocytes that are helping build insulating sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous.”

Zhang and his colleagues at the Waisman Center on the UW-Madison campus designed this experiment as a proof of principle investigation, but because they did not transplant enough dopamine-making cells into the brain, the animal’s behavior did not improve. Thus, although this transplant technique is certainly very promising, it is some ways from the clinic.

As noted by Emborg: “Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this technique improve the symptoms? Is it safe? Six months is not long enough.” Emborg continued, “And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem.”

Regardless of these shortcomings, this study still represents a genuine breakthrough. “By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine,” said Emborg.