Stemaid: The future of medicine

Umbilical cord stem cells may help treat people whose vision is damaged by a cloudy cornea, US research suggests.

The cornea is the transparent front part of the eye, which protects the delicate structures underneath and helps focus light.

But disease or injury can make it go cloudy, impairing vision, and corneas for transplant are in short supply.

A US team used human umbilical cord stem cells to treat laboratory mice with abnormally thin, cloudy corneas.

The University of Cincinnati study was presented at an American Society for Cell Biology conference.
“ These findings have the potential to create new and better treatments and an improved quality of life for patients with vision loss due to corneal injury ”
Dr Winston Kao University of Cincinnati

The mice had been bred to lack a protein essential for the formation and maintenance of a transparent cornea.

The cells - known as human umbilical cord mesenchymal stem cells (UMSCs) - have the ability to become any of a wide range of adult cell types.

They survived in the mouse cornea for three months with minimal signs of rejection.

They appeared to take on the properties of standard corneal cells called keratocytes.

Following the transplant, the thickness and transparency of the animals' corneas improved significantly.

In contrast, transplants using a different type of cell - human umbilical hematopoietic stem cells, which can give rise to all blood cell types - produced disappointing results.

They vanished rapidly from the mouse corneas when transplanted into the animals' eyes.

Easy to isolate

Lead researcher Dr Winston Kao said unlike donated corneas, the supply of UMSCs for use in transplants was almost unlimited.

He said the cells were easy to isolate from the umbilical cord, could be grown effectively in culture and stored easily in liquid nitrogen.

Dr Kao said: "Corneal transplantation is currently the only true cure for restoration of eyesight that may have been lost due to corneal scarring caused by infection, mechanical and chemical wounds and congenital defects of genetic mutations.

"Worldwide, there is a shortage of suitable corneas for transplantation.

"These findings have the potential to create new and better treatments and an improved quality of life for patients with vision loss due to corneal injury."

Dr Bruce Allan, a consultant ophthalmic surgeon at London's Moorfields Eye Hospital, said: "Access to cells to build new tissue-engineered corneal constructs may well lead to viable alternatives to conventional transplantation in future.

"The cornea is a relatively simple organ and cell therapies, including those based on mesenchymal stem cells, should ultimately succeed.

"But for the medium term at least, transplantation is likely to continue."

Dr Francisco Arnalich, another expert from Moorfields, has carried out similar work in rabbits using mesenchymal stem cells derived from fat tissue.

He said a US team had also had success using stem cells taken from human corneas.

He said: "There is still a long way to go from saying that they achieved clear corneas - moreover they just state that they improved transparency, not that they reach normal transparency - to say that this could be a substitute of corneal grafting."

French researchers say they have found a way of using human embryonic stem cells to create new skin which could help serious burns victims.

They say the stem cells grew into fully formed human skin 12 weeks after being grafted on to mice.

The researchers, writing in the Lancet journal, say the skin could solve the problems of rejection that burns patients currently face.

One stem cell expert said they had made an important advance.

Burns techniques

For more than 20 years, patients with serious burns have benefited from a technique which grows new skin in the laboratory using their own skin cells.

But the technique takes three weeks, putting the patients at risk of dehydration and infection.

Skin from cadavers is used during this period to cover the wounds but its availability is limited and it is often rejected by the patient's immune system.

Artificial nets which cells can grow on have also been tried. But they do not work on large burns, where they increase the risk of rejection and disease transmission because they can contain material from cows and other humans.

Skin formation

The researchers duplicated the biological steps that lead to skin formation during embryonic development.

They placed the calls on an artificial net which helped the cells to form a layer of skin.

This was grafted on to five mice and 12 weeks later, the skin had a structure consistent with human skin.

Dr Christine Baldeschi, from the Institute for Stem Cell Therapy and Exploration of Monogenic Diseases in Evry, France, who led the research, said the results were promising.

She said the technique could lead to "an unlimited resource for temporary skin replacement in patients with large burns awaiting grafts of their own skin".

Researchers are now planning a human trial of the new technique.

An accompanying editorial by Holger Schluter of the Peter MacCallum Cancer Centre in Melbourne, Australia, said the research represented an important advance.

He said: "This report takes research into regenerative skin stem cells to the next level.

"This finding suggests that skin derived from embryonic stem cells could be transplanted onto burnt patients awaiting skin grafts, with a reduced risk of rejection."

ScienceDaily (Nov. 10, 2009) — Human embryonic stem cells could help people with learning and memory deficits after radiation treatment for brain tumors, suggests a new UC Irvine study.

Research with rats found that transplanted stem cells restored learning and memory to normal levels four months after radiotherapy. In contrast, irradiated rats that didn't receive stem cells experienced a more than 50 percent drop in cognitive function.

"Our findings provide the first evidence that such cells can be used to ameliorate radiation-induced damage of healthy tissue in the brain," said Charles Limoli, UCI radiation oncology associate professor and senior author of the study, appearing online the week of Nov. 9 in the Proceedings of the National Academy of Sciences.

Radiotherapy for brain tumors is limited by how well the surrounding tissue tolerates the treatment. In receiving radiation at levels needed to treat tumors, patients suffer varying degrees of learning and memory impairment that can affect their quality of life.

"It's a progressive, debilitating side effect of cranial irradiation," Limoli said. "Any treatments showing promise at reversing this are worthy of pursuit."

In the UCI study, stem cells were transplanted into the heads of rats that had undergone radiation treatment. They migrated to a brain region known to support the growth of neurons, scientists observed, and developed into new brain cells.

Work is under way to determine how the transplanted stem cells improved cognition: Did they integrate into healthy tissue or did they help repair and support existing brain cells?

Said Limoli: "With further research, stem cells may one day be used to manage a variety of adverse conditions associated with radiotherapy."

In addition to Limoli, UCI scientists Munjal Acharya, Lori-Ann Christie, Mary Lan, Peter Donovan and Carl Cotman worked on this study, in collaboration with John Fike of UC San Francisco. The UCI researchers are from the departments of radiation oncology, biological chemistry, and developmental & cell biology; the Institute for Memory Impairments and Neurological Disorders, or UCI MIND; and the Sue & Bill Gross Stem Cell Research Center.

The study was supported by grants from the California Institute for Regenerative Medicine and the National Institutes of Health.

Human embryonic stem cells (hESCs) have potential as a vaccination against colon and other cancers, according to scientists at the University of Connecticut Stem Cell Institute. The group also discovered that while embryonic stem cells triggered a response, induced pluripotent stem cells (iPSC) did not.

The study was published online October 7 in the journal Stem Cells. The team injected laboratory mice with hESCs and discovered a consistent immune response against colon cancer cells. They report seeing a dramatic decline in tumor growth within the immunized mice. This revealed that immunized mice could generate a strong antitumor response through the application of hESCs.

“Cancer and stem cells share many molecular and biological features,” points out says Zihai Li, M.D., Ph.D., one of the study leaders. “By immunizing the host with stem cells, we are able to fool the immune system to believe that cancer cells are present and thus to initiate a tumor-combating immune program.”

The discovery builds upon a century-old theory that immunizing with embryonic materials may generate an antitumor response. “Although we have only tested the protection against colon cancer, we believe that stem cells might be useful for generating an immune response against a broad-spectrum of cancers thus serving as a universal cancer vaccine,” concludes Bei Liu, M.D., co-leader of the study.

By injecting stem cells directly into the brain, scientists have successfully reversed neural birth defects in mice whose mothers were given heroin during pregnancy. Even though most of the transplanted cells did not survive, they induced the brain's own cells to carry out extensive repairs.

Transplanted stem cells have previously shown promise in reversing brain damage caused by strokes, as well as by neurological diseases like Parkinson's, Alzheimer's, and Huntington's. But their use in treating birth defects is relatively new. In recent years, a handful of research teams have been developing stem-cell-based therapies for rodents with real or simulated birth defects in the brain.

Joseph Yanai, director of the Ross Laboratory for Studies in Neural Birth Defects at the Hebrew University-Hadassah Medical School, in Jerusalem, says that stem-cell therapies are ideal for treating birth defects where the mechanism of damage is multifaceted and poorly understood. "If you use neural stem cells," says Yanai, "they are your little doctors. They're looking for the defect, they're diagnosing it, and they're differentiating into what's needed to repair the defect. They are doing my job, in a way."

Yanai and his colleagues began with mice that had been exposed to heroin in the womb. These mice suffer from learning deficits; when placed in a tank of murky water, for instance, they take longer than normal mice to find their way back to a submerged platform. And in their hippocampus--an area of the brain associated with memory and navigation--critical biochemical pathways are disrupted, and fewer new cells are produced.

All of those problems are swiftly resolved when the researchers inject neural stem cells derived from embryonic mice into the brains of the heroin-exposed animals. When swimming, the treated mice caught up with their normal counterparts, and their cellular and biochemical deficits disappeared. Yanai announced these findings in 2007 and 2008.

Such dramatic results were surprising, considering that just a fraction of a percent of the transplanted stem cells survived inside the mice's brains. But they are consistent with an emerging consensus of how adult stem cells perform their many functions through so-called bystander or chaperone effects. Beyond simply generating replacements for damaged cells, stem cells seem to produce signals that spur other cells to carry out normal organ maintenance and initiate damage control.

"The chaperone effect is an important aspect of stem-cell biology that's simply been under-recognized," says Evan Snyder, who directs the Stem Cell Research Center at the Burnham Institute for Medical Research, in California, and whose research group coined the term in 2002. "That actually may be the low-hanging fruit in the stem-cell field--taking advantage of this, and not the cell-replacement aspect that we always thought would be the key to stem-cell biology in regenerative medicine."

Cesar Borlongan, a professor and vice chairman for research in the department of neurosurgery at the University of South Florida College of Medicine, uses a different model to explore the use of stem-cell treatment for brain-damaged infants. By deliberately restricting blood and oxygen flow to the brains of newborn rats, he and his colleagues simulate the effects of an infant stroke--a devastating event that causes untreatable brain injury in newborn humans.


Much like Yanai, Borlongan found that injecting stem cells into the compromised rats' brains reversed some of the behavioral deficits seen before treatment. For example, the treated rats could balance for longer time periods on a rotating rod.

To bring this kind of therapy closer to clinical tests in humans, Borlongan has experimented with administering the stem cells intravenously. Last July, in the online version of the Journal of Cerebral Blood Flow and Metabolism, he and his colleagues announced that transplanted stem cells produced the same result in rats regardless of whether they were given intravenously or injected directly into the brain.

Yanai has had similar success with intravenous administration in his heroin-exposure model, which he plans to announce at this year's annual meeting of the International Society for Stem Cell Research, in Barcelona.

The injected stem cells are able to migrate from the bloodstream to the brain for two reasons, says Borlongan. First, the injured brain sends out chemical signals that recruit the cells. And second, brain damage can compromise the blood-brain barrier, which normally regulates which substances can cross the threshold into the brain.

Not everyone is enthusiastic about the intravenous approach, however. Darwin Prockop, director of the Institute for Regenerative Medicine at Texas A&M Health Science Center College of Medicine, cautions that the injected cells can lodge in other organs--particularly the lungs--causing unwanted and even deadly side effects. And according to Evan Snyder, it may be unnecessary to go in through the bloodstream; his group has not seen any major risks associated with direct brain injection, a route that he considers to be clinically feasible in humans.

But all of these therapies involve introducing foreign cells into the body, and therefore, run the risk of provoking a potentially dangerous immune response. In most studies to date, the treated rodents are dosed with powerful immunosuppressants. Yanai is currently exploring personalized treatments to circumvent this issue: cells are extracted from the animal to be treated, coaxed to return to a stem-cell-like state, and then transplanted. Because they originate in the treated animal, the cells are recognized as "self" and ignored by the immune system.

Recently, Borlongan has found that immunosuppressants are unnecessary in the infant-stroke model. Because he treats the rodents at a very young age, their still-immature immune systems appear relatively unfazed by the transplanted stem cells. Borlongan notes that a low-level immune response may actually be useful: by cutting down on the number of cells that survive in the long term, it may reduce the chance that injected cells will reproduce uncontrollably and form tumors.

Nonetheless, according to Prockop, the risk of tumors is a serious concern with any stem-cell-based therapy. And while he is optimistic about the future of cell therapies for treating a wide variety of diseases, he urges caution and conscience when considering severe birth defects. "The big danger is that you can take a child who may be doomed to die in a few years, and make that child a lifelong invalid who needs continuing nursing care," he says. "So the prospects, if you think about them hard, are extremely worrisome. If you don't get a complete cure, you may be causing more harm than good."

ScienceDaily (Nov. 21, 2008) — Pluripotent stem cells — those, like embryonic stem cells, that give rise to almost every type of cell in the body — can be converted into the different classes of retinal cells necessary for vision, according to a new study from researchers at SUNY Upstate Medical University.

This research points to exciting new possibilities for preventing or reversing the disabling vision loss caused by age‑related macular degeneration, diabetes retinopathy, retinitis pigmentosa, glaucoma, and other diseases that damage the retina, the layer of light‑sensitive nerve cells that line the back of the eye. The research was presented at Neuroscience 2008, the annual meeting of the Society for Neuroscience in Washington, D.C.

“Vision is lost in these diseases because one or more of the seven retinal cell types die,” said the study’s lead author, Michael Ezra Zuber, Ph.D., assistant professor of ophthalmology and adjunct assistant professor of biochemistry and molecular biology at SUNY Upstate Medical University. “Current treatments can slow these diseases’ progression, but they can’t replace lost retinal cells. Pluripotent cells offer a promising starting point from which to generate new retinal cells.”

Zuber and his colleagues knew that cultured pluripotent cells could be induced to express some retinal cell genes, but they didn’t know if all retinal cell classes could be generated or if the cells would have the ability to form a functioning retina. To test that hypothesis, the scientists turned to pluripotent Xenopus laevis (frog) cells.

Under normal conditions, pluripotent frog cells form only skin tissue. The scientists were able, however, to convert the pluripotent cells to retinal cells by forcing them to express the eye field transcription factor (or EFTF) genes. The reprogrammed cells formed all seven classes of retinal cells normally found in the eyes, including the retinal ganglion cells, which have axons (optic nerves) that extend to the brain.

Furthermore, these new cells eventually formed into functioning eyes. When tested, tadpoles used their induced eyes to detect light and to engage in a vision‑based behavior. The scientists also found a population of self‑renewing cells in the periphery of the induced retinas, suggesting that EFTF‑induced cells also formed adult retinal stem cells.

“The goal of regenerative medicine is to replace dead or dying cells,” said Zuber. “The retina, like all body organs, contains multiple, distinct cell types. Therefore, successful recovery from blindness due to injury or disease will require the functional replacement of multiple retinal cell types. Our results demonstrate that pluripotent cells can be purposely altered to generate all the functional retinal cell classes necessary for vision.”

The research was supported by Research to Prevent Blindness, the E. Matilda Ziegler Foundation for the Blind, The Lions Club of Central New York, and the U.S. National Eye Institute.

The anti-inflammatory effect could lead to new therapies.
By Jennifer Chu

Until recently, the promise of stem-cell therapy has centered on stem cells' ability to morph into virtually any kind of cells. But researchers are finding that stem cells may have other healing effects. In recent studies, scientists have observed stem cells acting as anti-inflammatory agents, reducing swelling and even scarring when administered to injured tissue.

However, while stem cells' anti-inflammatory effects have been observed in a number of disease models, it has been difficult to pinpoint exactly how stem cells have this effect. Now a group at Tulane University, led by Darwin Prockop, director of the Center for Gene Therapy, has found that injecting human stem cells into the brains of stroke-induced mice triggers immune cells to produce chemicals that protect nerve cells, thereby reducing swelling and scarring. Prockop, now director of the Institute for Regenerative Medicine at Texas A&M Health Science Center, says that understanding the mechanism behind stem cells' anti-inflammatory effect could help researchers develop therapies for stroke and related diseases.

"In diabetes, Alzheimer's, and Parkinson's disease, there is an excessive early inflammatory response, and stem cells can sense that," says Prockop. "If you can turn that inflammation down, everything improves."

In their experiments, described in a paper published today in the Proceedings of the National Academy of Sciences, Prockop and his teaminduced a stroke in mice by blocking blood flow to their brains for 15 minutes. They then injected bone-marrow-derived human stem cells into the oxygen-deprived portion of the brains of some of the mice and observed the interactions between stem cells and the neural environment over a period of about two weeks.

Although the injected stem cells disappeared after just five days, the researchers found that they had a lasting effect on surrounding brain cells. Mice treated with stem cells experienced 60 percent less cell death compared with mice who did not receive the treatment.
Furthermore, when placed in an open environment, the treated mice behaved much like healthy mice, actively exploring the space around them, unlike their more lethargic untreated counterparts.

"It was a hit-and-run effect," says Prockop. "The human stem cells stopped some of the negative processes going on, and stopped the mouse brain from destroying itself."

To investigate further, the team analyzed genetic activity in samples of brain tissue before and after stem-cell injection. They found that 586 genes in the mouse brain were overactive in following brain injury and that 10 percent of these genes were dampened after stem-cell injection. Prockop found that many of these genes produce proteins involved in inflammation and immunity, and he hypothesizes that stem cells actually change the genetic instructions given out by brain cells in response to injury, reducing brain swelling that would otherwise occur.

To confirm the findings, the team also examined mouse brains for cytokines--proteins secreted by immune cells in response to injury. These proteins come in a variety of forms that can induce either inflammatory or anti-inflammatory effects. The researchers found that, following stem-cell injection, the affected brain area was flooded with insulin-like growth factor 1--an anti-inflammatory cytokine secreted by immune cells that protects the brain from blood-deprived injury, such as stroke. Other proteins indicating the presence of immune cells were also found in increased numbers, compared with untreated brain samples.

Identifying the various proteins that reduce inflammation could lead to new drugs that increase the production of such proteins to treat a variety of diseases, Prockop says. However, he believes that stem cells themselves may ultimately be a more effective therapeutic route. "You could find out all the proteins that are made, and give those to patients," says Prockop. "But you may get a better response with stem cells, because they have this marvelous ability to sense and adjust to their environment."

Eva Mezey, a National Institute of Health investigator who studies stem-cell interactions in the brain, agrees that stem cells may have broad applications in treating inflammation but cautions that they may not be the most effective therapy for stroke. "Almost every stroke is a little bit different, and a person may have other diseases, like diabetes," Mezey says. "There are so many other variables that it seems there isn't one drug that's efficacious in humans."

She adds that "stem cells may be a very promising new way in the treatment of a variety of diseases that are somehow related to immunity or inflammation, but they are not a therapy for stroke."

Copyright Technology Review 2008.

The treatment uses umbilical and marrow cells to help develop normal skin. Doctors say it may move his genetic disorder, recessive epidermolysis bullosa, 'off the incurable list' for other patients.

By Thomas H. Maugh II, Los Angeles Times Staff Writer
June 7, 2008

Using stem cells from umbilical cord blood and bone marrow, researchers have apparently cured a fatal genetic disease in a 2-year-old Minneapolis boy, which could open the door for other stem cell treatments.

For the first time in his life, Nate Liao is wearing normal clothes, eating food that has not been pureed, and playing with his siblings.

"Nate's quality of life is forever changed," said Dr. John Wagner of the University of Minnesota Medical School, who performed the treatment. "Maybe we can take one more disorder off the incurable list."

The team later treated Nate's 5-year-old brother, Jacob, and is preparing to treat 9-month-old Sarah Rose Mooreland of Folsom, Calif. Hopes are high for them as well.

Nate suffers from recessive epidermolysis bullosa, which affects 1 in 100,000 children. They lack a critical protein called collagen type VII that anchors the skin and lining of the gastrointestinal system to the body.

Their skin is extraordinarily fragile. Tearing and blistering occur with minimal friction, leading to painful wounds and scarring. Solid food produces erosion of the esophagus. Death usually results from malnutrition, infections or aggressive skin cancer.

The only treatment previously has been to wrap the skin in bandages.

The idea of using circulating stem cells to treat the condition was developed by Dr. Angela M. Christiano of Columbia University Medical Center. This is the first time that cells from bone marrow and cord blood have been used to treat a condition that does not involve blood.

Seven months after treatment, Nate's body is making collagen type VII, Wagner said at a news conference Tuesday. His face has plumped up and he has fewer blisters. "I have watched Nate improve every day," said his mother, Theresa.

The results will be published in a future issue of the New England Journal of Medicine.

04 March 2008

Human embryonic stem cells produce a protein which shows some anti-cancer properties in the lab, according to a new study.

The potential for stem-cell therapies to cause cancer is a major concern, but now researchers at Northwestern University in Chicago, US, say a protein produced by human embryonic stem cells (hESCs) can inhibit the growth and spread of breast cancer and malignant melanoma, the deadliest form of skin cancer.

They suspect that the protein, called Lefty, has similar effects on other tumour types, including those of the prostate.

The similarities between stem cells – primitive cells which can differentiate into the body’s different tissue types – and tumour cells have intrigued researchers. Both are self-renewing and have the capacity to give rise to different cells types.

The team at Northwestern previously showed that hESCs – the most versatile type of stem cell – produce chemicals that caused melanoma cells to revert to normal skin cells.

They also demonstrated that melanoma and breast cancers produce a protein called Nodal that helps tumour cells spread, and that this protein also facilitates embryonic stem cell's ability to turn into different cell types.

Tumours controlled
In the latest study they set out to find the substances produced by hESCs that have anti-cancer properties – perhaps, they believed, by blocking Nodal.

Lefty, the protein they identified, blocks the production of Nodal and therefore controls embryonic cell differentiation and development.

Mary Hendrix, who led the study, showed that unlike hESCs, however, tumour cells do not express Lefty. This allows them to produce Nodal in an unregulated manner – and to keep growing and spreading.

But when the researchers exposed aggressive tumour cells to the chemical environment of hESCs, which contained Lefty, levels of Nodal production fell sharply, and the tumour cells became less invasive and even started to die.

Hendrix told New Scientist she was optimistic that anti-cancer treatments based on stem cell proteins such as Lefty would emerge. "We now hope to interest pharmaceutical or biotech companies into developing partnerships to develop new treatments. We really believe that we are onto something important."

She adds that other stem cells proteins with anti-cancer effects probably remained to be discovered.

Embryonic source
Significantly, Hendrix notes that Lefty is secreted only by hESCs, and not by any other stem-cell type tested – including stem cells isolated from amniotic fluid, cord blood or adult bone marrow – or placental cells.

"After all the controversy about using embryonic stem cells, this shows how potentially important such research is," she says.

Lyle Armstrong at Newcastle University in the UK says the latest study is "convincing" in showing the prominent role the Nodal protein plays in aggressive cancers. He says more research is needed to see if other types of cancer respond equally well when the pathway is switched off.

"The paper clearly shows that factors which probably promote human embryonic stem cell proliferation are important in controlling tumour cell behaviour," notes Stephen Minger, director of the stem cell biology laboratory at Kings College London. "This provides a novel target for developing tumour cell therapies."

Journal reference: Proceedings of the National Academy of Sciences (DOI: 10.1073__pnas.0800467105)

Cancer - Learn more about one of the world’s biggest killers in our comprehensive special report.

Stem Cells - Learn more about the promise and the controversy in our cutting edge special report .

Published: Feb. 12, 2008 at 12:56 PM

DALLAS, Feb. 12 (UPI) -- Balloons and signs greeted 2-year-old Caden Ledbetter's return from the hospital following a rare stem cell cancer treatment, a Dallas newspaper said.

Doctors with the Medical City Dallas Hospital released Caden Monday following a two-month treatment for neuroblastoma, a cancer of the nervous system.

Doctors used chemotherapy to treat the cancer and then used stem cells from Caden's umbilical cord to rebuild his immune system, The Dallas Morning News said Tuesday. The treatment is so rare doctors are unsure whether the cancer will stay in remission or develop again from the umbilical cells.

"We're not talking about his being cured of his neuroblastoma right now," said Dr. Joel Weinthal who treated the boy. "It's certainly a very positive thing that he gets to go home from the hospital but he has a long road ahead of him."

The Ledbetters put air purifiers and a new circulation system in their house to help protect Caden's new immune system and he will undergo more radiation treatments for cancer.

His mother told the Morning News that Caden didn't talk to anyone at the hospital "and everything was 'No, don't touch me,'" but she added that, "Now we're almost back to the Caden that we know."