Category Archives: Stem Cells

Apr. 22, 2013 UCLA researchers led by Carla Koehler, professor of chemistry and biochemistry and Dr. Michael Teitell, professor of pathology and pediatrics, both members of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research and the Jonsson Comprehensive Cancer Center, have discovered a new agent that may be useful in strategies to remove pluripotent stem cells that fail-to-differentiate from their progeny, tissue-specific cells, potentially resulting in safer therapies for patients.

The study was published online ahead of press April 15, 2013 in Developmental Cell.

Pluripotent stem cells can become any cell in the body. When stem cells are differentiated into specific daughter cells such as nerve, muscle, or bone cells, not all of the stem cells differentiate, leaving some pluripotent stem cells mixed in with the differentiated cells. Because of the pluripotent stem cell's ability to become any cell type in the body, these cells can also become unintended cells such as bone in blood, or form tumors called teratomas. Therefore, identifying and removing pluripotent stem cells from the differentiated cells before using daughter cells is of utmost importance in stem cell-based therapeutics. Current methods for removing pluripotent stem cells are limited.

Studies in the model system Saccharomyces cerevisiae, simple baker's yeast, by Koehler, Teitell, and colleagues discovered a molecule called MitoBloCK-6 that inhibits assembly of the mitochondria, which are the power plants of cells. As the group moved to more complex systems, they showed that MitoBloCK-6 blocked cardiac development in the model organism, zebrafish. However, MitoBloCK-6 had no effect on differentiated cell lines that are typically cultured in the lab. "I was puzzled by this result, because we thought this pathway was essential for all cells regardless of differentiation state," said Koehler.

Post-doctoral fellow Deepa Dabir meticulously tested the compound on many differentiated cell lines, but the results were still the same: The cells remained healthy. Then the team decided to test MitoBloCK-6 on human pluripotent stem cells. Post-doctoral fellow Kiyoko Setoguchi showed that the pluripotent stem cells died in the presence of MitoBloCK-6, but shortly after differentiation, the daughter cells were resistant to death.

MitoBloCK-6 caused the pluripotent stem cells to die by triggering apoptosis, a process of cell suicide. The death of pluripotent stem cells left a population of differentiated cells, thus potentially reducing the risks of teratoma and other problems that would limit their use as a regenerative medicine treatment strategy.

"We discovered that pluripotent stem cell mitochondria undergo a change during differentiation into tissue-specific daughter cells," said Teitell, "which could be the key to the survival of the differentiated cells when the samples are exposed to MitoBloCK-6. We are still investigating this process in mitochondria, but we now know that mitochondria have an important role in controlling pluripotent stem cell survival."

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Method makes it easier to separate useful stem cells from 'problem' ones for therapies

WASHINGTON: Scientists have for the first time transformed human embryonic stem cells into nerve cells to help mice regain the ability to learn and remember. The study by the University of Wisconsin-Madison in US is the first to show that human stem cells can successfully implant themselves in the brain and then heal neurological deficits.

Once inside the mouse brain, the implanted stem cells formed two common, vital types of neurons, which communicate with the chemicals GABA or acetylcholine.

"These two neuron types are involved in many kinds of human behaviour, emotions, learning, memory, addiction and many other psychiatric issues," said senior author Su-Chun Zhang, a professor of neuroscience and neurology.

The human embryonic stem cells were cultured in the lab, using chemicals that are known to promote development into nerve cells. After the transplant, the mice scored significantly better on common tests of learning and memory in mice.

The study began with deliberate damage to a part of the brain that is involved in learning and memory.

"Developing brain cells get their signals from the tissue that they reside in, and the location in the brain we chose directed these cells to form both GABA and cholinergic neurons," Zhang said. The initial destruction was in an area called the medial septum, which connects to the hippocampus by GABA and cholinergic neurons.

"This circuitry is fundamental to our ability to learn and remember," Zhang said. The transplanted cells, however, were placed in the hippocampus, a vital memory center. After the transferred cells were implanted, in response to chemical directions from the brain, they started to specialize and connect to the appropriate cells in the hippocampus.

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Implanting stem cells into brain can restore memory

Mika Ono 858-784-2052 mikaono@scripps.edu

Newswise LA JOLLA, CA April 22, 2013 In a serendipitous discovery, scientists at The Scripps Research Institute (TSRI) have found a way to turn bone marrow stem cells directly into brain cells.

Current techniques for turning patients marrow cells into cells of some other desired type are relatively cumbersome, risky and effectively confined to the lab dish. The new finding points to the possibility of simpler and safer techniques. Cell therapies derived from patients own cells are widely expected to be useful in treating spinal cord injuries, strokes and other conditions throughout the body, with little or no risk of immune rejection.

These results highlight the potential of antibodies as versatile manipulators of cellular functions, said Richard A. Lerner, the Lita Annenberg Hazen Professor of Immunochemistry and institute professor in the Department of Cell and Molecular Biology at TSRI, and principal investigator for the new study. This is a far cry from the way antibodies used to be thought ofas molecules that were selected simply for binding and not function.

The researchers discovered the method, reported in the online Early Edition of the Proceedings of the National Academy of Sciences the week of April 22, 2013, while looking for lab-grown antibodies that can activate a growth-stimulating receptor on marrow cells. One antibody turned out to activate the receptor in a way that induces marrow stem cellswhich normally develop into white blood cellsto become neural progenitor cells, a type of almost-mature brain cell.

Natures Toolkit

Natural antibodies are large, Y-shaped proteins produced by immune cells. Collectively, they are diverse enough to recognize about 100 billion distinct shapes on viruses, bacteria and other targets. Since the 1980s, molecular biologists have known how to produce antibodies in cell cultures in the laboratory. That has allowed them to start using this vast, target-gripping toolkit to make scientific probes, as well as diagnostics and therapies for cancer, arthritis, transplant rejection, viral infections and other diseases.

In the late 1980s, Lerner and his TSRI colleagues helped invent the first techniques for generating large libraries of distinct antibodies and swiftly determining which of these could bind to a desired target. The anti-inflammatory antibody Humira, now one of the worlds top-selling drugs, was discovered with the benefit of this technology.

Last year, in a study spearheaded by TSRI Research Associate Hongkai Zhang, Lerners laboratory devised a new antibody-discovery techniquein which antibodies are produced in mammalian cells along with receptors or other target molecules of interest. The technique enables researchers to determine rapidly not just which antibodies in a library bind to a given receptor, for example, but also which ones activate the receptor and thereby alter cell function.

Lab Dish in a Cell

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Antibody Transforms Stem Cells Directly into Brain Cells

Apr. 22, 2013 Individual cancer cells that break away from the original tumor and circulate through the blood stream are considered responsible for the development of metastases. These dreaded secondary tumors are the main cause of cancer-related deaths. Circulating tumor cells (CTCs) detectable in a patient's blood are associated with a poorer prognosis. However, up until now, experimental evidence was lacking as to whether the "stem cell" of metastasis is found among CTCs.

"We were convinced that only very few of the various circulating tumor cells are capable of forming a secondary tumor in a different organ, because many patients do not develop metastases even though they have cancer cells circulating through their blood," says Prof. Andreas Trumpp, a stem cell expert. Trumpp is head of DKFZ's Division of Stem Cells and Cancer and director of the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) at DKFZ. "Metastasis is a complex process and cancer cells need to have very specific properties for it. Our hypothesis was that the characteristics of cancer stem cells, which are resistant to therapy and very mobile, are best suited," says Trumpp.

Irne Baccelli from Trumpp's team developed a transplantation test for experimental detection of metastasis-initiating cells. In collaboration with Prof. Andreas Schneeweiss from the National Center for Tumor Diseases (NCT) Heidelberg along with colleagues from the Institute of Tumor Biology in Hamburg and the Institute of Pathology of Heidelberg University Hospitals, the researchers analyzed the blood of more than 350 breast cancer patients. Using specific surface molecules, Baccelli isolated circulating tumor cells from the blood and directly transplanted them into the bone marrow of mice with defective immune systems. "Bone marrow is a perfect niche for tumor sells to colonize," Trumpp explains. After more than one hundred transplantations, metastases actually started forming in the bones, lungs and livers of some of the animals.

This proved that CTCs do contain metastasis stem cells -- even though apparently with a low frequency. What characterizes these cells? To characterize their molecular properties, the researchers analyzed the surface molecules of those CTCs where the cell transplantation had led to metastases.

Three molecules characterize the metastasis stem cell

In a systematic screening process, Baccelli first isolated cells carrying a typical protein of breast cancer stem cells (CD44) on their surface from the CTCs. This protein helps the cell to settle in bone marrow. Next, the researchers screened this cell population for specific surface markers which help the cells to survive in foreign tissue. These include, for example, a signaling molecule that protects from attacks by the immune system (CD47) and a surface receptor that enhances the cells' migratory and invasive capabilities (MET).

Using a cell sorter, the researchers were then able to isolate those CTCs which exhibit all three characteristics (CD44, CD47, MET) at once. Another round of transplantation tests showed that these really were the cells from which the metastases originated.

Depending on the patient, cells exhibiting all three surface molecules ("triple-positive" cells) made up between 0.6 and 33 percent of all CTCs. "It is interesting that only cells with the stem cell marker CD44 carry the combination of the other two surface molecules," said Irne Baccelli. "It looks like the triple-positive cells are a specialized subtype of breast cancer stem cells circulating in the blood."

Triple-positive cells as prognostic biomarkers

Are the triple-positive cells a more precise biomarker of breast cancer progression than the number of CTCs alone? In a small patient group, the researchers observed that as the disease advances, the number of triple-positive cells increases, but the total number of CTCs does not. In addition, patients with very high numbers of triple-positive cells had particularly high numbers of metastases and a much poorer prognosis than women in whom only few of these metastasis-inducing cells were detected. "On the whole, triple-positive cells seem to have a substantially higher biological relevance for disease progression than previously studied CTCs," Andreas Schneeweiss explains. The researchers plan to confirm these new results in a large study.

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Metastasis stem cells in the blood of breast cancer patients discovered

Public release date: 21-Apr-2013 [ | E-mail | Share ]

Contact: Suzanne Price sprice@nutrition.org 617-954-3976 Federation of American Societies for Experimental Biology

Boston, MARudolf Jaenisch of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology will speak at EB 2013 on the topic of stem cells, pluripotency and nuclear reprogramming. His work has led to major advances in our understanding of embryonic stem cells and "induced pluripotent stem" (IPS) cells, which appear identical to embryonic stem cells but can be created from adult cells without using an egg. Dr. Jaenisch will discuss the mechanism of in vitro reprogramming and the inefficiency of gene targeting on Sunday, April 21at 2:30 pm at the meeting of the American Association of Anatomists at Experimental Biology.

The stem cell field is no stranger to controversy and has become widely discussed for the cells' ability to generate any cell type. They offer a new way to study human development. "The greatest interest in using stem cells is for disease research," said Jaenisch. "In the late 1990s when Dolly was cloned, it was called therapeutic cloning. It is considered controversial for using human eggs and is technically difficult. With IPS cells, we now have a way to study the pathogenesis of disease in petri dishes, without human eggs."

According to Jaenisch, where Dolly was a theoretical solution, we now have new technology that makes it possible to move into application. IPS cells will allow scientists to study complex human diseases in Petri dishes, a step toward analyzing the conditions and developing therapies.

Another potential benefit from IPS cells is to use them for transplantation into a patient to cure disease possibly. "We can likely find a way to reduce the risk of organ/tissue rejection. We can also correct mutations in IPS cells," he added, which gives researchers one less complicating factor.

Jaenisch received his doctorate in medicine from the University of Munich in 1967. Before coming to Whitehead, he was head of the Department of Tumor Virology at the Heinrich Pette Institute at the University of Hamburg. He has coauthored more than 375 research papers and has received numerous prizes and recognitions, including an appointment to the National Academy of Sciences in 2003. He received the 2011 National Medal of Science.

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About Experimental Biology 2013

Experimental Biology's mission is to share the newest scientific concepts and research findings shaping future and current clinical advances and to give scientists and clinicians an unparalleled opportunity to hear from colleagues working on similar biomedical problems using different disciplines. With six sponsoring societies and another 20 U.S. and international guest societies, the annual meeting brings together scientists from throughout the United States and the world, representing dozens of scientific areas, from laboratory to translational to clinical research. The meeting also offers a wide spectrum of professional development sessions.

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Using induced pluripotent stem cells, scientists can better study human disease

MONTCLAIR, N.J., April 16, 2013 /PRNewswire/ --A preliminary research study, which found that adult stem cells may be functionally reprogrammed to act like younger cells, was presented by Dr. Vincent Giampapa at The Second International Vatican Stem Cell Conference: Regenerative Medicine A Fundamental Shift in Science and Culture, from within the Vatican, held between April 11-13, 2013. The research, which has potential implications in the restoration of human immune function, was conducted by researchers affiliated with CellHealth Institute.

(Logo:http://photos.prnewswire.com/prnh/20130327/LA84207LOGO)

Dr. Vincent Giampapa, chief medical officer of CellHealth Institute, faculty at UMDNJ's Medical School, and principal investigator of the research, revealed that the preliminary findings support further research into the reprogramming of adult stem cells. This research could lead to a major breakthrough in treating chronic illnesses, enhancing immune response and the maintenance of optimal health.

"Although this is a pilot study, this is the first time that adult stem cells have been functionally reprogrammed to act as younger versions of themselves," said Dr. Giampapa. "The implications for future use in the restoration of immune function as well as the cell regeneration in aging humans is plausible. It's early days, but the signs are there to give us great hope as we move forward into the next phases of research."

CellHealth Institute and its research is supported by key investors, including John Malone, chairman of Liberty Media Corporation, and Dr. Ed Bosarge, founder and CEO of Capital Technologies Inc. The preliminary research study was funded by Dr. Bosarge, through the Bosarge Family Office. Dr. Bosarge will also fund the next stage of the research, which is scheduled to take place in the coming months.

About CellHealth InstituteCellHealthInstitute(CHI)is a biotechnology company focused on cellular health that integrates breakthrough products and services with holistic lifestyle education.CHI collaborates with top-tier research universities and publicly traded biotech companies to offer fully integrated personalized health programs paired with scientific biomarker evaluations, as well as medical-grade supplements, including everycell,and advanced treatment through stem cell therapies. The organization is headquartered in New Jersey with an international regenerative medicine destination in Costa Rica set to open in 2014. CHI services and products allowpeopleto take control of their own health at the most basic level their cells.

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Preliminary Research, Led By Dr. Vincent Giampapa, Finds Aged Adult Stem Cells Can Be Functionally Reprogrammed To Act ...

Durham, NC (PRWEB) April 16, 2013

Can stem cell therapy outperform a drug commonly considered the gold standard for treating rheumatoid arthritis? A new study in rodents published in the current issue of STEM CELLS Translational Medicine indicates perhaps so.

The findings could lead to a faster, safer, more effective way to bring relief to the up to 70 million people estimated to suffer from this disease worldwide.

Rheumatoid arthritis (RA) is a chronic condition that causes pain, stiffness, swelling and limited motion and function of many joints. While it can affect any joint, RA tends to settle mainly in a patients hands and feet. The results can be debilitating.

People who have RA overproduce a protein called tumor necrosis factor (TNF), which causes the inflammation and damage to the bones, cartilage and tissue. Anti-TNF drugs can block the action of the protein and reduce inflammation. Etanercept (marketed under the trade name Enbrel) is a type of anti-TNF drug called a biologic that for years has been prescribed to treat RA. However, it cant be targeted specifically to the site of the arthritis and, thus, requires higher doses that can cause serious side effects including fatal infections, multiple sclerosis, seizures, heart failure, cancer and more.

Moreover, biologics in general require intense development and manufacturing processes that are challenging for reproducibility, even within the same company. So we wanted to see how delivering treatment through a very targeted system such as that which can be done using stem cells compared to a biologic drug such as Etanercept, said Joseph Mosca, Ph.D. He led the team of researchers from Osiris Therapeutics, Inc. Baltimore, Md., and the Novartis Research, Basel, Switzerland, in conducting the study.

The researchers began by genetically altering human mesenchymal stem cells (MSCs) in the lab to become vehicles for the cell-based anti-TNF delivery. They then injected the cells into mice that had been induced with RA and monitored them over a seven-day period, then compared the results to a group of animals treated with Etanercept. The results showed that the anti-TNF therapy delivered by stem cells reversed or attenuated the arthritis inflammation on par with the Etanercept except that it did it faster.

If this translates into fewer side-effects and/or lower compliance remains to be seen, Dr. Mosca said. In either case, these results illustrate the ability of stem cells to deliver proteins of therapeutic value and demonstrate their potential clinical utility in rheumatoid/osteoarthritis and other TNF-related diseases where anti-TNF biologic drugs have already shown promise.

The authors have shown the feasibility of a targeted approach to treatment using cells that are known to home to damaged tissue, said Anthony Atala, M.D., Editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. The manuscript supports and demonstrates the potential of mesenchymal stem cells as a vehicle for cell-based gene delivery.

### The full article, Comparison of Drug and Cell-Based DeliveryEngineered Adult Mesenchymal Stem Cells Expressing Soluble Tumor Necrosis Factor Receptor-II Prevent Arthritis in Mouse and Rat Animal Models, can be accessed at http://www.stemcellstm.com.

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Stem Cells Might Beat Drugs in Delivering Relief Faster, More Effectively to Rheumatoid Arthritis Sufferers