Category Archives: Stem Cells

Parkinson #39;s Disease- Dr. Ashworth Discusses How Stem Cells Helped his Parkinson #39;s Disease
Dr. Ashworth came to Dr. Steenblock to help with his Parkinson #39;s Disease. He got amazing results after having a stem cell treatment. To learn more about how ...

By: David Steenblock

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Parkinson's Disease- Dr. Ashworth Discusses How Stem Cells Helped his Parkinson's Disease - Video

(This story is an update of my earlier blog post on the controversy over whether the stress-created STAP cells actually exist).

A stunning stem cell breakthrough announced last month is being examined for errors by the institute where the studys lead researcher works.

The Riken Institute in Japan has launched an investigation into the study, it told news outlets including the journal Nature, which published the study Jan. 29. The probe was launched after other stem cell researchers, who have failed to replicate the findings, are expressing growing doubt.

The study, led by Haruko Obokata of Riken, found that certain white cells from young mice could be easily converted into embryonic-like or pluripotent stem cells by immersing them in acid or subjecting them to other stresses.

Stem cell researcher Paul Knoepfler / California Institute for Regenerative Medicine

The creation of what the researchers called STAP cells appeared to be a great advance from existing methods used to create what are called induced pluripotent stem cells. The IPS methods require adding genes and chemicals and convert just a small percentage of cells treated.

But scientists examining the study said it apparently used inverted and duplicate images. These included one indicating that the cells grew a placenta, a sure sign that stem cells had been produced. Riken declined to say specifically which allegations it was investigating, according to the news reports.

Additionally, scientists including UC Davis stem cell researcher Paul Knoepfler said the finding appeared very unlikely. Pluripotent stem cells tend to form tumors, so producing them in response to stress should have been weeded out by evolution, Knoepfler wrote on his blog, ipscell.com. Hes also running an informal poll.

Weve had nine people put reports of various kinds there, and none of the reports seemed particularly encouraging, Knoepfler said in a Tuesday interview.

"There's a feeling that the duplication of the placenta image, which now one of the authors has confirmed was indeed a duplication, and also some duplication of data in a paper in 2011 by (co-author Charles) Vacanti and Obokata, has made people more concerned about their level of confidence in the finding overall," Knoepfler said.

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Doubts mount on STAP stem cells

New research from the University of Michigan Comprehensive Cancer Center and Georgia Regents University finds that a protein that fuels an inflammatory pathway does not turn off in breast cancer, resulting in an increase in cancer stem cells. This provides a potential target for treating triple negative breast cancer, the most aggressive form of the disease.

The researchers identified a protein, SOCS3, that is highly expressed in normal cells but undetectable in triple-negative breast cancer. They showed that this protein is degraded in cancers, blocking the cellular off-switch of a feedback loop involving the inflammatory protein interleukin 6, IL6. When the switch does not get turned off, it enables cancer stem cells to grow.

"We have known for a long time known that there are important links between inflammation and cancer, including similar pathways that regulate normal and cancer stem cells," says study author Max S. Wicha, M.D., distinguished professor of oncology and director of the U-M Comprehensive Cancer Center.

"This work helps explain why these pathways shut off in normal tissues after injury but remain active in cancers, resulting in an increase in cancer stem cells. Furthermore, they suggest that blocking these inflammatory loops may be a means of targeting cancer stem cells, improving patient outcome," he says.

The study appears in the Nature journal Oncogene.

Currently, there are no molecularly targeted therapies aimed at triple-negative breast cancer, which is a type of cancer negative for estrogen receptor, progesterone receptor and the HER2 protein -- all key targets for current therapies. Patients with this form of disease tend to have worse outcomes.

The researchers tested a drug, bortezomib, in mouse models of triple-negative breast cancer and found that it stops the protein degradation, resulting in the inflammatory loop shutting off, which reduces the cancer stem cells, thereby blocking metastasis. Bortezomib is currently approved for treatment of the blood cancer multiple myeloma.

This team previously showed that IL6 can stimulate breast cancer stem cells in HER2-positive breast cancers and they are designing a clinical trial which uses an IL6 blocker. The new research suggests that adding bortezomib to the IL6 inhibitor may be a way to target stem cells in triple-negative breast cancer.

"Now that we unveiled how inflammation is regulated in triple-negative breast cancer, we expect that our studies can be translated into the clinic. The drugs used to block these chemical messengers are already approved for the treatment of rheumatoid arthritis and other inflammation-related diseases, which should facilitate their use in cancer," says study author Hasan Korkaya, Ph.D., assistant professor at the Georgia Regents University Cancer Center.

More laboratory testing is needed before a clinical trial can begin. The researchers also suspect that this pathway may apply to other cancers as well and are investigating that further.

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Potential options for attacking stem cells in triple-negative breast cancer

A proposed Parkinson's disease treatment from stem cells is on track for an application to be filed with federal regulators around the start of 2015, International Stem Cell Corp. said Tuesday.

The Carlsbad-based company said the U.S. Food and Drug Administration had met with researchers for guidance on what steps need to be taken before filing an application. The meeting went about as expected, said Simon Craw, executive vice president. Ongoing animal studies must be completed, along with safety testing. FDA officials discussed details such as the number of animals to be tested and how the safety studies are to be conducted, Craw said.

International Stem Cell's treatment consists of progenitor cells that mature into neural cells, including those making the neurotransmitter dopamine. These neurons are destroyed in the disease, causing progressive paralysis.

The progenitor cells are to be implanted into the brains of Parkinson's patients, where they are expected to make dopamine and protect the remaining dopamine-making neurons. They are derived from unfertilized, or parthenogenetic, human egg cells, made to grow without fertilization.

Human parthenogenetic neural stem cells in the process of differentiating into dopamine-producing neurons. / International Stem Cell Corp.

Interim data from tests in primates are expected in March, and final results later in the year. The Investigational New Drug application, or IND, is expected to be filed a short while thereafter, Craw said. Filing before year's end "would be a stretch," Craw said; the filing is more likely to take place in early 2015.

Shares of International Stem Cell closed Tuesday after the announcement at 24 cents, up 7 percent for the day. The company is working with outside scientists; including D. Eugene Redmond Jr., who is leading a pharmacology/toxicology study. Parkinson's expert Mark Stacy at Duke University will lead the clinical trial. Evan Y. Snyder, a stem cell expert at Sanford-Burnham Medical Research Institute, assists as a scientific advisor.

The company's approach is similar to one being studied by scientists at The Scripps Research Institute led by Jeanne Loring. Moreover, both are expected to ask approval to begin trials around the same time.

Loring's group gets its cells from the patients to be treated, "reprogrammed" back to an embryonic-like state and called induced pluripotent stem cells, then differentiated into the neural progenitor cells. That treatment's main advantage is the use of the patients' own or autologous cells, expected to minimize any possible immune reaction.

The two groups know each other. Craw said International Stem Cell has hired some of Loring's students, and they have collaborated on some research.

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Intl. Stem Cell readies for Parkinson's study

PALO ALTO, Calif., Feb. 17 (UPI) -- In an experiment with mice, U.S. scientists say they've enabled muscle recovery in elderly mice by rejuvenating stem cells within their muscle tissue.

Normal aging is accompanied by a diminished ability to regain strength and mobility after muscle injury because over time stem cells within muscle tissues dedicated to repairing damage become less able to generate new muscle fibers and struggle to self-renew, researchers at Stanford University reported Sunday.

"In the past, it's been thought that muscle stem cells themselves don't change with age, and that any loss of function is primarily due to external factors in the cells' environment," Helen Blau of the university's school of medicine said.."However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles."

However, Blau and her colleagues say they've identified for the first time a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells.

"Our findings identify a defect inherent to old muscle stem cells," she said. "Most exciting is that we also discovered a way to overcome the defect. As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage."

The researchers used drugs to block elevated biological activity within the stem cells that causes them to degenerate into non-stem, muscle progenitor cells.

When transplanted back into the animal, the treated, rejuvenated stem cells migrate to their natural niches and provide a long-lasting stem cell reserve to contribute to repeated demands for muscle repair, they researchers said.

"In mice, we can take cells from an old animal, treat them for seven days -- during which time their numbers expand dramatically, as much as 60-fold -- and then return them to injured muscles in old animals to facilitate their repair," Blau said.

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Scientists 'rejuventate' stem cells in elderly mice to repair muscles

Claims by a Japanese research team that it made pluripotent stem cells simply by exposing normal mouse cells to acid baths and other stresses are now being investigated for "alleged irregulaties," according to an online article Monday in the journal Nature.

Mouse cells exposed to an acidic environment turned into embryonic-like "STAP" cells. These were used to generate an entire fetus. / Haruko Obokata

The study itself was published in Nature on Jan. 29. It gained widespread acclaim, but a number of scientists expressed doubts about the STAP cells on second thought. UC Davis stem cell researcher Paul Knoepfler gave his reasons for skepticism in a Feb. 6 blog post. Among his reasons: Evolution should have selected against such a mechanism, because cellular stress is a common part of life, and pluripotent stem cells produce tumors.

At the very least, researchers who have tried to replicate the findings aren't having an easy time doing so, according to an unscientific poll Knoepfler is running. The trend has turned from mostly positive to evenly split, Knoepfler reported in the second week of polling.

"Its also notable that respondents from Japan have shifted the most in opinion. In week 1 they were disproportionately positive, while in week 2 they became disproportionately negative," Knoepfler wrote.

Jeanne Loring, the TSRI stem cell researcher who I interviewed when the discovery was first announced, told me earlier this month that her lab, "along with everyone else in the universe," was trying to replicate the results.

"What I told my lab was, go ahead and do it; don't tell me about it until you have results, and don't let it interfere with the rest of your work," Loring said.

Life scientists from other fields weighed in on Twitter with their skepticism.

"Acid bath makes stem cells??? If it looks too good to be true, it probably is," wrote tart-tongued evolutionary biologist Dan Graur, who notably applied acid to claims by the ENCODE project (in its press release) that 80 percent of the human genome is functional.

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Acid test for STAP cells

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Health & Medicine for Senior Citizens

Older Muscle Stem Cells Rejuvenated to Function Like Younger Cells, May Help Elderly Repair Muscle

Stanford researchers pinpoint why normal aging is accompanied by a diminished ability to regain strength and mobility after muscle injury

By Krista Conger

Feb. 17, 2014 - Researchers at the Stanford University School of Medicine have pinpointed why normal aging is accompanied by a diminished ability to regain strength and mobility after muscle injury: Over time, stem cells within muscle tissues dedicated to repairing damage become less able to generate new muscle fibers and struggle to self-renew.

In the past, its been thought that muscle stem cells themselves dont change with age, and that any loss of function is primarily due to external factors in the cells environment, said Helen Blau, PhD, the Donald and Delia B. Baxter Foundation Professor.

However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles.

Blau and her colleagues also identified for the first time a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells. Our findings identify a defect inherent to old muscle stem cells, she said. Most exciting is that we also discovered a way to overcome the defect. As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage.

Blau, a professor of microbiology and immunology and director of Stanfords Baxter Laboratory for Stem Cell Biology, is the senior author of a paper describing the research, published online Feb. 16 in Nature Medicine. Postdoctoral scholar Benjamin Cosgrove, PhD, and former postdoctoral scholar Penney Gilbert, PhD, now an assistant professor at the University of Toronto, are the lead authors.

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Older Muscle Stem Cells Rejuvenated to Function Like Younger Cells, May Help Elderly Repair Muscle

Researchers at the Stanford University School of Medicine have pinpointed why normal aging is accompanied by a diminished ability to regain strength and mobility after muscle injury: Over time, stem cells within muscle tissues dedicated to repairing damage become less able to generate new muscle fibers and struggle to self-renew.

A release from the university quotes Helen Blau PhD, the Donald and Delia B. Baxter Foundation Professor, as saying, "In the past, it's been thought that muscle stem cells themselves don't change with age, and that any loss of function is primarily due to external factors in the cells' environment. However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles."

The release explains that Blau and her colleagues also identified for the first time a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells. "Our findings identify a defect inherent to old muscle stem cells," she said. "Most exciting is that we also discovered a way to overcome the defect. As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage."

Blau, a professor of microbiology and immunology and director of Stanford's Baxter Laboratory for Stem Cell Biology, is the senior author of a paper describing the research, which was published online Feberuary 16th 2014 in Nature Medicine. Postdoctoral scholar Benjamin Cosgrove, PhD, and former postdoctoral scholar Penney Gilbert, PhD, now an assistant professor at the University of Toronto, are the lead authors. The researchers found that many muscle stem cells isolated from mice that were two years old, equivalent to about 80 years of human life, exhibited elevated levels of activity in a biological cascade called the p38 MAP kinase pathway. This pathway impedes the proliferation of the stem cells and encourages them to instead become non-stem, muscle progenitor cells. As a result, although many of the old stem cells divide in a dish, the resulting colonies are very small and do not contain many stem cells. Using a drug to block this p38 MAP kinase pathway in old stem cells (while also growing them on a specialized matrix called hydrogel) allowed them to divide rapidly in the laboratory and make a large number of potent new stem cells that can robustly repair muscle damage, Blau said. "Aging is a stochastic but cumulative process," Cosgrove said. The word stochastic mean a process involving chance or probability. Cosgorce added that the team has shown that muscle stem cells progressively lose their stem cell function during aging. This treatment does not turn the clock back on dysfunctional stem cells in the aged population, he said. Rather, it stimulates stem cells from old muscle tissues that are still functional to begin dividing and self-renew."

The researchers found that, when transplanted back into the animal, the treated stem cells migrate to their natural niches and provide a long-lasting stem cell reserve to contribute to repeated demands for muscle repair. "In mice, we can take cells from an old animal, treat them for seven days during which time their numbers expand dramatically, as much as 60-fold and then return them to injured muscles in old animals to facilitate their repair," Blau said. In 2010, Blau's laboratory published a study in Science showing that muscle stem cells grown on soft hydrogel maintain their "stemness" in culture. In contrast, muscle stem cells grown on hard plastic tissue culture plates, the standard way to cultivate cells in the laboratory, quickly differentiate into more-specialized, but less therapeutically useful, muscle progenitor cells. The difference is likely due to the fact that soft hydrogel is more similar than rigid plastic to the muscle tissue environment in which the stem cells are naturally found. In the current study, the researchers found that targeting the p38 MAP kinase to induce the rapid expansion of the remaining functional stem cells from old mice required the soft hydrogel substrate. "The drug plus hydrogel boosts the small clones so that they undergo a burst of self-renewing divisions," Gilbert said. Thus, rejuvenation of the population is contingent on the synergy between biophysical and biochemical cues.

Finally, the researchers tested the ability of the rejuvenated old muscle stem cell population to repair muscle injury and restore strength in 2-year-old recipient mice. They teamed up with co-author Scott Delp, PhD, the James H. Clark Professor in the School of Engineering, who has designed a novel way to measure muscle strength in animals that had muscle injuries and then underwent the stem cell therapy. "We were able to show that transplantation of the old treated muscle stem cell population repaired the damage and restored strength to injured muscles of old mice," Cosgrove said. "Two months after transplantation, these muscles exhibited forces equivalent to young, uninjured muscles. This was the most encouraging finding of all." The researchers plan to continue their research to learn whether this technique could be used in humans. "If we could isolate the stem cells from an elderly person, expose them in culture to the proper conditions to rejuvenate them and transfer them back into a site of muscle injury, we may be able to use the person's own cells to aid recovery from trauma or to prevent localized muscle atrophy and weakness due to broken bones," Blau said. "This really opens a whole new avenue to enhance the repair of specific muscles in the elderly, especially after an injury. Our data pave the way for such a stem cell therapy."

### Other Stanford authors of the study include postdoctoral scholar Ermelinda Porpiglia, PhD; instructor Foteini Mourkioti, PhD; undergraduate student Steven Lee; senior research scientist Stephane Corbel, PhD; and medical resident Michael Llewellyn, MD, PhD. The research was supported by the National Institutes of Health (grants R25CA118681, K99AG042491, T32CA009151, K99AR061465, U01HL100397, U01HL099997, R01AG020961, R01HL096113 and R01AG009521), the California Institute for Regenerative Medicine and the Baxter Foundation.

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Rejuvenated Stem Cells Help Aging Muscles Heal

TOKYO: A Japanese research institute on Tuesday said itwas probing its own study that promised a 'game changer' way to create stem cells, a feat hailed as revolutionary for the fast-developing field.

The findings, published by Japanese researcher Haruko Obokata and American partners in a January edition of the British journal Nature, outlined a simple and low-tech approach in the quest to grow transplant tissue in the lab.

The national institute Riken said Tuesday it had started an investigation over "questions" about the methodology and input data of the study, appointing several in-house and outside experts to pore over the revolutionary report. Obokata works for the institute.

At issue are allegations that the researchers used erroneous image data for the high-profile article, local media reported.

"The experts have already started hearings for the researchers involved in the articles," an institute spokesman said Tuesday, but declined to give further details.

For the moment, the institute is standing by the results -- a spokesman insisted the "findings themselves are unassailable."

Stem cells are primitive cells that, as they grow, differentiate into the various specialised cells that make up the different organs -- the brain, the heart, kidney and so on.

The goal is to create stem cells in the lab and nudge them to grow into these differentiated cells, thus replenishing organs damaged by disease or accident.

The researchers' groundbreaking findings said that white blood cells in newborn mice were returned to a versatile state by incubating them in a solution with high acidity for 25 minutes, followed by a five minute spin in a centrifuge and a seven-day spell of immersion in a growth culture.

Called stimulus-triggered acquisition of pluripotency (STAP) cells, the innovation breaks new ground.

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'Game changing' Japan stem-cell study questioned

PUBLIC RELEASE DATE:

16-Feb-2014

Contact: Bradley Olwin bradley.olwin@colorado.edu 303-492-6816 University of Colorado at Boulder

New findings on why skeletal muscle stem cells stop dividing and renewing muscle mass during aging points up a unique therapeutic opportunity for managing muscle-wasting conditions in humans, says a new University of Colorado Boulder study.

According to CU-Boulder Professor Bradley Olwin, the loss of skeletal muscle mass and function as we age can lead to sarcopenia, a debilitating muscle-wasting condition that generally hits the elderly hardest. The new study indicates that altering two particular cell-signaling pathways independently in aged mice enhances muscle stem cell renewal and improves muscle regeneration.

One cell-signaling pathway the team identified, known as p38 MAPK, appears to be a major player in making or breaking the skeletal muscle stem cell, or satellite cell, renewal process in adult mice, said Olwin of the molecular, cellular and developmental biology department. Hyperactivation of the p38 MAPK cell-signaling pathway inhibits the renewal of muscle stem cells in aged mice, perhaps because of cellular stress and inflammatory responses acquired during the aging process.

The researchers knew that obliterating the p38 MAPK pathway in the stem cells of adult mice would block the renewal of satellite cells, said Olwin. But when the team only partially shut down the activity in the cell-signaling pathway by using a specific chemical inhibitor, the adult satellite cells showed significant renewal, he said. "We showed that the level of signaling from this cellular pathway is very important to the renewal of the satellite cells in adult mice, which was a very big surprise," said Olwin.

A paper on the subject appeared online Feb. 16 in the journal Nature Medicine.

One reason the CU-Boulder study is important is that the results could lead to the use of low-dose inhibitors, perhaps anti-inflammatory compounds, to calm the activity in the p38 MAPK cell-signaling pathway in human muscle stem cells, said Olwin.

The CU-Boulder research team also identified a second cell-signaling pathway affecting skeletal muscle renewal a receptor known as the fibroblast growth factor receptor-1, or FGFR-1. The researchers showed when the FGFR-1 receptor protein was turned on in specially bred lab mice, the renewal of satellite cells increased significantly. "We still don't understand how that particular mechanism works," he said.

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CU-Boulder stem cell research may point to new ways of mitigating muscle loss