Stem Cell Clinic

First test of pluripotent stem cell therapy in monkeys is a success

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15-May-2014

Contact: Mary Beth O'Leary moleary@cell.com 617-397-2802 Cell Press

Researchers have shown for the first time in an animal that is more closely related to humans that it is possible to make new bone from stem-cell-like induced pluripotent stem cells (iPSCs) made from an individual animal's own skin cells. The study in monkeys reported in the Cell Press journal Cell Reports on May 15th also shows that there is some risk that those iPSCs could seed tumors, but that unfortunate outcome appears to be less likely than studies in immune-compromised mice would suggest.

"We have been able to design an animal model for testing of pluripotent stem cell therapies using the rhesus macaque, a small monkey that is readily available and has been validated as being closely related physiologically to humans," said Cynthia Dunbar of the National Heart, Lung, and Blood Institute. "We have used this model to demonstrate that tumor formation of a type called a 'teratoma' from undifferentiated autologous iPSCs does occur; however, tumor formation is very slow and requires large numbers of iPSCs given under very hospitable conditions. We have also shown that new bone can be produced from autologous iPSCs, as a model for their possible clinical application."

Autologous refers to the fact that the iPSCs capable of producing any tissue typein this case bonewere derived from the very individual that later received them. That means that use of these cells in tissue repair would not require long-term or possibly toxic immune suppression drugs to prevent rejection.

The researchers first used a standard recipe to reprogram skin cells taken from rhesus macaques. They then coaxed those cells to form first pluripotent stem cells and then cells that have the potential to act more specifically as bone progenitors. Those progenitor cells were then seeded onto ceramic scaffolds that are already in use by reconstructive surgeons attempting to fill in or rebuild bone. And, it worked; the monkeys grew new bone.

Importantly, the researchers report that no teratoma structures developed in monkeys that had received the bone "stem cells." In other experiments, undifferentiated iPSCs did form teratomas in a dose-dependent manner.

The researchers say that therapies based on this approach could be particularly beneficial for people with large congenital bone defects or other traumatic injuries. Although bone replacement is an unlikely "first in human" use for stem cell therapies given that the condition it treats is not life threatening, the findings in a primate are an essential step on the path toward regenerative clinical medicine.

"A large animal preclinical model for the development of pluripotent or other high-risk/high-reward generative cell therapies is absolutely required to address issues of tissue integration or homing, risk of tumor formation, and immunogenicity," Dunbar said. "The testing of human-derived cells in vitro or in profoundly immunodeficient mice simply cannot model these crucial preclinical safety and efficiency issues."

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First test of pluripotent stem cell therapy in monkeys is a success

Stem Cell Therapy Shows Promise for MS in Mouse Model

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Newswise LA JOLLA, CAMay 15, 2014Mice crippled by an autoimmune disease similar to multiple sclerosis (MS) regained the ability to walk and run after a team of researchers led by scientists at The Scripps Research Institute (TSRI), University of Utah and University of California (UC), Irvine implanted human stem cells into their injured spinal cords.

Remarkably, the mice recovered even after their bodies rejected the human stem cells. When we implanted the human cells into mice that were paralyzed, they got up and started walking a couple of weeks later, and they completely recovered over the next several months, said study co-leader Jeanne Loring, a professor of developmental neurobiology at TSRI.

Thomas Lane, an immunologist at the University of Utah who co-led the study with Loring, said he had never seen anything like it. Weve been studying mouse stem cells for a long time, but we never saw the clinical improvement that occurred with the human cells that Dr. Loring's lab provided, said Lane, who began the study at UC Irvine.

The mices dramatic recovery, which is reported online ahead of print by the journal Stem Cell Reports, could lead to new ways to treat multiple sclerosis in humans.

"This is a great step forward in the development of new therapies for stopping disease progression and promoting repair for MS patients, said co-author Craig Walsh, a UC Irvine immunologist.

Stem Cell Therapy for MS

MS is an autoimmune disease of the brain and spinal cord that affects more than a half-million people in North America and Europe, and more than two million worldwide. In MS, immune cells known as T cells invade the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating on nerve fibers called myelin. Affected nerve fibers lose their ability to transmit electrical signals efficiently, and this can eventually lead to symptoms such as limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression.

Current therapies, such as interferon beta, aim to suppress the immune attack that strips the myelin from nerve fibers. But they are only partially effective and often have significant adverse side effects. Lorings group at TSRI has been searching for another way to treat MS using human pluripotent stem cells, which are cells that have the potential to transform into any of the cell types in the body.

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Stem Cell Therapy Shows Promise for MS in Mouse Model

First test of pluripotent stem cell therapy in monkeys is successful

By Uncategorized

Researchers have shown for the first time in an animal that is more closely related to humans that it is possible to make new bone from stem-cell-like induced pluripotent stem cells (iPSCs) made from an individual animal's own skin cells. The study in monkeys reported in the Cell Press journal Cell Reports on May 15th also shows that there is some risk that those iPSCs could seed tumors, but that unfortunate outcome appears to be less likely than studies in immune-compromised mice would suggest.

"We have been able to design an animal model for testing of pluripotent stem cell therapies using the rhesus macaque, a small monkey that is readily available and has been validated as being closely related physiologically to humans," said Cynthia Dunbar of the National Heart, Lung, and Blood Institute. "We have used this model to demonstrate that tumor formation of a type called a 'teratoma' from undifferentiated autologous iPSCs does occur; however, tumor formation is very slow and requires large numbers of iPSCs given under very hospitable conditions. We have also shown that new bone can be produced from autologous iPSCs, as a model for their possible clinical application."

Autologous refers to the fact that the iPSCs capable of producing any tissue typein this case bonewere derived from the very individual that later received them. That means that use of these cells in tissue repair would not require long-term or possibly toxic immune suppression drugs to prevent rejection.

The researchers first used a standard recipe to reprogram skin cells taken from rhesus macaques. They then coaxed those cells to form first pluripotent stem cells and then cells that have the potential to act more specifically as bone progenitors. Those progenitor cells were then seeded onto ceramic scaffolds that are already in use by reconstructive surgeons attempting to fill in or rebuild bone. And, it worked; the monkeys grew new bone.

Importantly, the researchers report that no teratoma structures developed in monkeys that had received the bone "stem cells." In other experiments, undifferentiated iPSCs did form teratomas in a dose-dependent manner.

The researchers say that therapies based on this approach could be particularly beneficial for people with large congenital bone defects or other traumatic injuries. Although bone replacement is an unlikely "first in human" use for stem cell therapies given that the condition it treats is not life threatening, the findings in a primate are an essential step on the path toward regenerative clinical medicine.

"A large animal preclinical model for the development of pluripotent or other high-risk/high-reward generative cell therapies is absolutely required to address issues of tissue integration or homing, risk of tumor formation, and immunogenicity," Dunbar said. "The testing of human-derived cells in vitro or in profoundly immunodeficient mice simply cannot model these crucial preclinical safety and efficiency issues."

The NIH team is now working with collaborators on differentiation of the macaque iPSCs into liver, heart, and white blood cells for eventual clinical trials in hepatitis C, heart failure, and chronic granulomatous disease, respectively.

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The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.

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First test of pluripotent stem cell therapy in monkeys is successful

Human stem cell treatment helps mice with MS-like condition walk again

By Stem Cell Treatment

Home > News > world-news

Washington, May 16 : Mice severely disabled by a condition that was similar to multiple sclerosis (MS) were able to walk less than two weeks following treatment with human neural stem cells.

In striking contrast to active, healthy mice, those with an MS-like condition must be fed by hand because they cannot stand long enough to eat and drink on their own. When scientists transplanted human neural stem cells into the MS mice, they expected no benefit from the treatment. They thought the mice would reject the cells, much like rejection of an organ transplant.

Co-senior author, Tom Lane, Ph.D., a professor of pathology at the University of Utah, said my postdoctoral fellow Dr. Lu Chen came to me and said, 'The mice are walking.' I didn't believe her.

He began the study with co-first author Chen at the University of California, Irvine.

Within a remarkably short period of time, 10 to 14 days, the mice had regained motor skills. Six months later, they showed no signs of slowing down.

The findings have been published online in the journal Stem Cell Reports.

--ANI (Posted on 16-05-2014)

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Human stem cell treatment helps mice with MS-like condition walk again

MS mice walk after stem cell treatment

By Stem Cell Treatment

Treatment with human stem cells has allowed mice crippled by a version of multiple sclerosis to walk again after less than two weeks.

Scientists admit to being astonished by the result and believe it opens up a new avenue of research in the quest for solutions to MS.

Prof Tom Lane, from the University of Utah, who led the US team, recalled: My postdoctoral fellow Dr Lu Chen came to me and said the mice are walking. I didnt believe her.

The mice had a condition that mimics the symptoms of human MS. They were so disabled they could not stand long enough to eat and drink and had to be hand-fed.

The scientists transplanted human neural stem cells into the mice expecting them to be rejected. But within 10 to 14 days, the mice had regained motor skills and were able to walk again.

Six months later, they showed no sign of relapsing.

The findings, published in the journal Stem Cell Reports, suggest the mice experienced at least a partial reversal of their symptoms.

A similar outcome in humans could help patients with potentially disabling progressive stages of the disease for which there are no treatments.

This result opens up a whole new area of research for us to figure out why it worked, said co-author Dr Jeanne Loring, director of the Center for Regenerative Medicine at The Scripps Research Institute in La Jolla, California.

Weve long forgotten our original plan.

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MS mice walk after stem cell treatment

Stem cell therapy shows promise for multiple sclerosis

By Stem Cell Treatment

In this image, the top row shows the stem cells transplanted into the mouse spinal cord. The lower row shows a close-up of the stem cells (brown). By day 7 post-transplant, the stem cells are no longer detectable. Within this short period of time, the stem cells have sent chemical signals to the mouses own cells, enabling them to repair the nerve damage caused by MS. (image: Lu Chen)

For patients with multiple sclerosis (MS), current treatment options only address early-stage symptoms of the debilitating disease. Now, new research has found a potential treatment that could both stop disease progression and repair existing damage.

In a study published in Stem Cell Reports, researchers utilized a group of paralyzed mice genetically engineered to have an MS-like condition. Initially, the researchers set out to study the mechanisms of stem cell rejection in the mice. However, two weeks after injecting the mice with human neural stem cells, the researchers made the unexpected discovery that the mice had regained their ability to walk.

This had a lot of luck to do with it; right place, right time co-senior author Jeanne Loring, director of the Center for Regenerative Medicine at The Scripps Research Institute in La Jolla, California, told FoxNews.com. [co-senior author Tom Lane] called me up and said, Youre not going to believe this. He sent me a video, and it showed the mice running around the cages. I said, Are you sure these are the same mice?

Loring, whose lab specializes in turning human stem cells into neural precursor cells, or pluripotent cells, collaborated with Tom Lane, a professor of pathology at the University of Utah whose focus is on neuroinflammatory diseases of the central nervous system. The team was interested in stem cell rejection in MS models in order to understand the underlying molecular and cellular mechanisms contributing to rejection of potential stem cell therapies for the disease.

Multiple sclerosis is an autoimmune disease that affects more than 2.3 million people worldwide. For people with MS, the immune system misguidedly attacks the bodys myelin, the insulating coating on nerve fibers.

In a nutshell, its the rubber sheath that protects the electrical wire; the axon that extends from the nerves cell body is insulated by myelin, Lane, who began the study while at the University of California, Irvine, told FoxNews.com

Once the myelin has been lost, nerve fibers are unable to transmit electric signals efficiently, leading to symptoms such as vision and motor skill problems, fatigue, slurred speech, memory difficulties and depression.

The researchers inadvertent treatment appeared to work in two ways. First, there was a decrease of inflammation within the central nervous system of the mice, preventing the disease from progressing. Secondly, the injected cells released proteins that signaled cells to regenerate myelin and repair existing damage.

While the stem cells were rejected in the mice after 10 days, researchers were able to see improvements for up to six months after initial implantation.

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Stem cell therapy shows promise for multiple sclerosis

Mice with multiple sclerosis-like condition walk again after human stem cell treatment

By Stem Cell Treatment

Mice severely disabled by a multiple sclerosis (MS) -- like condition could walk less than two weeks following treatment with human stem cells. The finding, which uncovers new avenues for treating MS, will be published online on May 15, 2014, in the journal Stem Cell Reports.

When scientists transplanted human stem cells into MS mice, they predicted the cells would be rejected, much like rejection of an organ transplant.

Expecting no benefit to the mice, they were surprised when the experiment yielded spectacular results.

"My postdoctoral fellow Dr. Lu Chen came to me and said, 'The mice are walking.' I didn't believe her," said co-senior author, Tom Lane, Ph.D., a professor of pathology at the University of Utah, who began the work at University of California, Irvine.

Within just 10 to 14 days, the mice regained motor skills. Six months later, they still showed no signs of slowing down.

"This result opens up a whole new area of research for us," said co-senior author Jeanne Loring, Ph.D., co-senior author and professor at The Scripps Research Institute in La Jolla, Calif.

More than 2.3 million people worldwide have MS, a disease where the immune system attacks myelin, an insulation layer surrounding nerve fibers. The resulting damage inhibits nerve impulses, producing symptoms that include difficulty walking, impaired vision, fatigue and pain.

The MS mice treated with human stem cells experience a reversal of symptoms. Immune attacks are blunted, and damaged myelin is repaired, explaining their dramatic recovery. The discovery could help patients with latter, or progressive, stages of the disease, for whom there are no treatments.

Counterintuitively, the researchers' original prediction that the mice would reject the stem cells, came true. There are no signs of the cells after one week. In that short window, they send chemical signals that instruct the mouse's own cells to repair the damage caused by MS. This realization could be important for therapy development.

"Rather than having to engraft stem cells into a patient, which can be challenging, we might be able to put those chemical signals into a drug that can be used to deliver the therapy much more easily," said Lane.

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Mice with multiple sclerosis-like condition walk again after human stem cell treatment

Stem Cells to The Rescue: Repairing The Hearts

By Stem Cell Doctors

FRESNO, Calif. (KFSN) --

"Grace is what's carried me through this," Minch told Ivanhoe.

Ten years ago, at just 49, the choir singer and her husband were told she would need a quadruple bypass.

"Now we are at the point where my heart is severely damaged and nothing is really helping," Minch said.

Doctors said a heart transplant was her only option, but she'll soon find out if she'll be accepted into a new trial that could use her own stem cells to help repair the once thought irreversible damage, "or even create new blood vessels within areas of the heart that have been damaged," Jon George, MD, Interventional Cardiologist, Temple University School of Medicine, told Ivanhoe.

First, stem cells are taken from a patient's bone marrow. Then using a special catheter and 3D mapping tool, the cells are injected directly into the damaged tissue.

"We have results from animal data that show blood vessels regrow in the patients that actually get stem cell therapy," Dr. George said.

It's a possible answer to Debbie's prayers.

Temple University Hospital is currently pre-screening patients for the trial. For more information, call 215-707-5340.

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Stem Cells to The Rescue: Repairing The Hearts

Enzyme helps stem cells improve recovery from limb injuries

By Stem Cell Medicine

While it seems like restoring blood flow to an injured leg would be a good thing, it can actually cause additional damage that hinders recovery, researchers say.

Ischemia reperfusion injury affects nearly two million Americans annually with a wide variety of scenarios that temporarily impede blood flow -- from traumatic limb injuries, to heart attacks, to donor organs, said Dr. Babak Baban, immunologist at the Medical College of Georgia and College of Dental Medicine at Georgia Regents University.

Restoring blood flow actually heightens inflammation and cell death rather than recovery for many of these patients.

"Think about trying to hold onto a nuclear power plant after you unplug the electricity and cannot pump water to cool it down," said Dr. Jack Yu, Chief of MCG's Section of Plastic and Reconstructive Surgery. "All kinds of bad things start happening."

Baban and Yu are collaborators on a study published in the journal PLOS ONE that shows one way stem cell therapy appears to intervene is with the help of an enzyme also used by a fetus to escape rejection by the mother's immune system.

Earlier studies indicate stem cells may improve recovery both by enabling new blood vessel growth and by turning down the now-severe inflammation, Baban said. The new study shows that indoleomine 2,3 dioxygenase, or IDO, widely known to dampen the immune response and create tolerance, plays an important role in regulating inflammation in that scenario. Stems cells and numerous other cell types are known to express IDO.

In fact, IDO boosted stem cell efficacy by about a third in their studies in animal models comparing the therapy in normal mice versus mice missing IDO. The researchers documented decreased expression of inflammatory markers, swelling and cell death, which correlate with a shorter, improved recovery.

That could be just what the doctor ordered for these patients, said Baban, the study's corresponding author. "We don't want to turn off the immune system, we want to turn it back to normal," he said.

Problems start with even a short period of inadequate blood and nutrients resulting in the rapid accumulation of destructive acidic metabolites, free radicals, and damage to cell structures, Yu said. Cell power plants, called mitochondria, which should be producing the energy source ATP, are among the early casualties, quickly becoming fat, leaky, and dysfunctional.

"The mitochondria are sick; they are very, very sick," Yu said. When blood flow is restored, it can put huge additional stress on sick powerhouses.

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Enzyme helps stem cells improve recovery from limb injuries

A Fetal Enzyme Helps Stem Cells Recover From Limb Injuries

By Stem Cell Medicine

April Flowers for redOrbit.com Your Universe Online

Nearly two million Americans a year suffer from ischemia reperfusion injuries. A wide variety of scenarios can be caused by these injuries that result in restricted blood flowfrom traumatic limb injuries, to heart attacks, to donor organs. Restoring the blood flow to an injured leg, for example, seems like it would be a good idea. A new study from Georgia Regents University, however, suggests that restoring the flow could cause additional damage that actually hinders recovery.

Rather than promoting recovery, restoring blood flow actually heightens inflammation and cell death for many of these patients.

Think about trying to hold onto a nuclear power plant after you unplug the electricity and cannot pump water to cool it down, said Dr. Jack Yu, Chief of MCGs Section of Plastic and Reconstructive Surgery. All kinds of bad things start happening.

Yu collaborated with Dr. Babak Baban, immunologist at the Medical College of Georgia and College of Dental Medicine at Georgia Regents University. Their study, published in PLOS ONE, reveals that one way stem cell therapy appears to intervene is with the help of an enzyme also used by a fetus to escape rejection by the mothers immune system.

Baban notes that previous studies have found a correlation between stem cells and recovery. The stem cells both enable new blood vessel growth and by turning down the now-severe inflammation. The new findings reveal that ndoleomine 2,3 dioxygenase, or IDO, widely known to dampen the immune response and create tolerance, plays an important role in regulating inflammation in that scenario. IDO is expressed by stem cells and numerous other cell types.

Stem cell efficiency was boosted by approximately one-third when tested on animal models comparing the therapy in normal mice versus mice missing IDO.Decreased expression of inflammatory markers, swelling and cell death were all observed. These are all associated with shorter, improved recoveries.

We dont want to turn off the immune system, we want to turn it back to normal, Baban said.

Even a brief period of inadequate blood flow, and the resulting lack of nutrients, can start problems that result in the rapid accumulation of destructive acidic metabolites, free radicals, and damage to cell structures. Mitochondria, which are the cells power plants, should be producing the energy source ATP. Instead, they quickly become fat, leaky and dysfunctional in this situation.

The mitochondria are sick; they are very, very sick, Yu said. Enormous additional stress is added to these sick powerhouses when blood flow is restored.

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A Fetal Enzyme Helps Stem Cells Recover From Limb Injuries

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