ScienceDaily (July 23, 2012) Stem cells hold great promise for the medicine of the future, but they can also be a cause of disease. When these self-renewing, unspecialized cells fail to differentiate into diverse cell types, they can start dividing uncontrollably, leading to cancer. Already several decades ago, Weizmann Institute scientists were among the first to demonstrate the link between cancer and the faulty differentiation of stem cells. Now a new Weizmann Institute-led study, published in Molecular Cell, reveals a potential molecular mechanism behind this link.

The scientists managed to uncover the details of a step in the process of DNA "repackaging" that takes place during embryonic stem cell differentiation. It turns out that for the cells to differentiate properly, certain pieces of the packaging of their DNA must be labeled by a molecular tag called ubiquitin. Such tagging is required for turning on a group of particularly long genes, which enable the stem cell to differentiate. The researchers identified two switches: An enzyme called RNF20 enhances the tagging, whereas a second enzyme, USP44, does the opposite, shutting it down. Furthermore, it appears that both these switches must operate properly for the differentiation process to proceed efficiently. When the scientists interfered with the tagging -- either by disabling the "ON" switch RNF20, or by deregulating the activity of the "OFF" switch USP44 -- the stem cells failed to differentiate.

These experiments might explain the significance of molecular defects identified in a number of cancers, for example, the abnormally low levels of RNF20 in certain breast and prostate cancers and the excess of USP44 in certain leukemias. Notably, faulty differentiation of stem cells is often a hallmark of the more aggressive forms of cancer. This research was led by Prof. Moshe Oren of the Molecular Cell Biology Department, with Prof. Eytan Domany of the Physics of Complex Systems Department and Dr. Jacob Hanna of the Molecular Genetics Department. The team included Weizmann Institute's Gilad Fuchs, Efrat Shema, Rita Vesterman, Eran Kotler, Sylvia Wilder, Lior Golomb, Ariel Pribluda and Ester Feldmesser, as well as Zohar Wolchinsky of the Technion -- Israel Institute of Technology; Feng Zhang and Xiaochun Yu of the University of Michigan in the US; Mahmood Haj-Yahya and Ashraf Brik of Ben-Gurion University of the Negev; and Daniel Aberdam of the Technion and the University of Nice-Sophia Antipolis in France.

This study belongs to a relatively new direction in cancer research: Rather than focusing on the genes involved, it highlights the role of epigenetics -- that is, processes that do not modify the gene code, itself, but affect the way its information is interpreted within the cell. Understanding the epigenetic roots of cancer will advance the search for effective therapies for this disease.

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Judging DNA by its cover: Explaining the link between stem cells and cancer

CLEVELAND, Ohio-- Imagine cooking up a new recipe for carrot cake and trying to figure out what it tastes like by feeding it to your dog. You might be able to learn something from his reactions -- Does he eat some? A lot? Does he, heaven forbid, keel over afterward? -- but you'd be pretty limited by some basic differences between you and your canine friend. Even if he could somehow tell you what he thinks, there's just no telling if cake tastes the same to a dog.

This is something like the problem faced by researchers who are trying to understand and treat devastating human brain diseases like Parkinson's and Huntington's by working with mice.

The mouse brain has told us a lot about the diseases, but, in the end, it's only a stand-in for working with the real thing.

Now the real thing is here. Two groups of Parkinson's and Huntington's researchers working in 13 labs nationwide have used advanced stem-cell technology to make human brain cells from skin cells donated by patients with those diseases. The brain cells look and act like cells affected by the diseases, and they can be manipulated in a petri dish.

Working with the new cells in a petri dish is a little like taking a bite of your recipe and getting your own reaction, without the potential of making yourself sick.

It's a first for the field, says Dr. Christopher Ross, one of the Huntington's disease study's lead researchers and professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine in Baltimore.

"It's going to be a tremendous opportunity to study the disease, to understand it, and particularly to develop therapeutics," he says.

Huntington's disease is inherited and caused by a defect in a single gene. The disease is progressive and fatal, causing twitching and jerking movement, dementia and brain-cell death. It affects about 30,000 people in the United States. Parkinson's, while not fatal, affects about 1 million Americans and causes progressively worsening movement problems as well as mood and sleep disruptions.

The technology that made the recent advance possible, called induced pluripotent stem cells, or iPSCs, was developed about four years ago simultaneously at the University of Wisconsin and in Japan.

In short, iPSCs are adult cells (usually skin or blood cells) taken from a donor with the disease and then genetically reprogrammed, or induced, back to their most primitive state. Once they are turned into stem cells, they can be forced to develop into any cell in the human body.

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Parkinson's, Huntington's disease research makes advances with stem cells: Discoveries

Public release date: 23-Jul-2012 [ | E-mail | Share ]

Contact: Yivsam Azgad news@weizmann.ac.il 972-893-43856 Weizmann Institute of Science

Stem cells hold great promise for the medicine of the future, but they can also be a cause of disease. When these self-renewing, unspecialized cells fail to differentiate into diverse cell types, they can start dividing uncontrollably, leading to cancer. Already several decades ago, Weizmann Institute scientists were among the first to demonstrate the link between cancer and the faulty differentiation of stem cells. Now a new Weizmann Institute-led study, published in Molecular Cell, reveals a potential molecular mechanism behind this link.

The scientists managed to uncover the details of a step in the process of DNA "repackaging" that takes place during embryonic stem cell differentiation. It turns out that for the cells to differentiate properly, certain pieces of the packaging of their DNA must be labeled by a molecular tag called ubiquitin. Such tagging is required for turning on a group of particularly long genes, which enable the stem cell to differentiate. The researchers identified two switches: An enzyme called RNF20 enhances the tagging, whereas a second enzyme, USP44, does the opposite, shutting it down. Furthermore, it appears that both these switches must operate properly for the differentiation process to proceed efficiently. When the scientists interfered with the tagging either by disabling the "ON" switch RNF20, or by deregulating the activity of the "OFF" switch USP44 the stem cells failed to differentiate.

These experiments might explain the significance of molecular defects identified in a number of cancers, for example, the abnormally low levels of RNF20 in certain breast and prostate cancers and the excess of USP44 in certain leukemias. Notably, faulty differentiation of stem cells is often a hallmark of the more aggressive forms of cancer. This research was led by Prof. Moshe Oren of the Molecular Cell Biology Department, with Prof. Eytan Domany of the Physics of Complex Systems Department and Dr. Jacob Hanna of the Molecular Genetics Department. The team included Weizmann Institute's Gilad Fuchs, Efrat Shema, Rita Vesterman, Eran Kotler, Sylvia Wilder, Lior Golomb, Ariel Pribluda and Ester Feldmesser, as well as Zohar Wolchinsky of the Technion Israel Institute of Technology, Feng Zhang and Xiaochun Yu of the University of Michigan in the US, Mahmood Haj-Yahya and Ashraf Brik of Ben-Gurion University of the Negev, and Daniel Aberdam of the Technion and the University of Nice-Sophia Antipolis in France.

This study belongs to a relatively new direction in cancer research: Rather than focusing on the genes involved, it highlights the role of epigenetics that is, processes that do not modify the gene code, itself, but affect the way its information is interpreted within the cell. Understanding the epigenetic roots of cancer will advance the search for effective therapies for this disease.

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Prof. Eytan Domany's research is supported by the Kahn Family Research Center for Systems Biology of the Human Cell, which he heads; the Mario Negri Institute for Pharmacological Research - Weizmann Institute of Science Exchange Program; the Leir Charitable Foundations; and Mordechai Segal, Israel. Prof. Domany is the incumbent of the Henry J. Leir Professorial Chair.

Dr. Jacob Hanna's research is supported by the Leona M. and Harry B. Helmsley Charitable Trust; Pascal and Ilana Mantoux, France/Israel; the Sir Charles Clore Research Prize; Erica A. Drake and Robert Drake; and the European Research Council.

Prof. Moshe Oren's research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Robert Bosch Foundation; the estate of Harold Z. Novak; and the European Research Council. Prof. Oren is the incumbent of the Andre Lwoff Professorial Chair in Molecular Biology.

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Judging DNA by its cover

MOBILE, Alabama -- Damaged and aged heart tissue of older heart failure patients was rejuvenated by stem cells modified by scientists, according to research presented today at the American Heart Associations Basic Cardiovascular Sciences 2012 Scientific Sessions in New Orleans.

The study is simultaneously published in the Journal of the American College of Cardiology. The stem cell research could lead to new treatments for heart failure patients, researchers said.

Since patients with heart failure are normally elderly, their cardiac stem cells arent very healthy, said Sadia Mohsin, Ph.D., one of the study authors and a post-doctoral research scholar at San Diego State Universitys Heart Institute in San Diego.

We modified these biopsied stem cells and made them healthier. It is like turning back the clock so these cells can thrive again.

Modified human stem cells helped the signaling and structure of the heart cells, which were biopsied from elderly patients, according to information provided by the American Heart Association.

Researchers modified the stem cells in the laboratory with PIM-1, a protein that promotes cell survival and growth. Cells were rejuvenated when the modified stem cells enhanced activity of an enzyme called telomerase, which elongates telomere length.

Telomeres are caps on the ends of chromosomes that aid cell replication. Aging and disease results when telomeres break off.

There is no doubt that stem cells can be used to counter the aging process of cardiac cells caused by telomere degradation, Mohsin said in a statement.

The technique increased telomere length and activity, as well as increasing cardiac stem cell proliferation, all vital steps in combating heart failure, health officials have said.

While human cells were used, the research was limited to the laboratory. Researchers have tested the technique in mice and pigs and found that telomere lengthening leads to new heart tissue growth in about four weeks.

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Stem cells used to rejuvenate damaged heart tissue, study shows

Study Highlights :

Embargoed until: 4 p.m. CT/5 p.m. ET Monday, July 23, 2012

NEW ORLEANS, July 23, 2012 (GLOBE NEWSWIRE) -- Damaged and aged heart tissue of older heart failure patients was rejuvenated by stem cells modified by scientists, according to research presented at the American Heart Association's Basic Cardiovascular Sciences 2012 Scientific Sessions.

The study is simultaneously published in the Journal of the American College of Cardiology.

The research could one day lead to new treatments for heart failure patients, researchers said.

"Since patients with heart failure are normally elderly, their cardiac stem cells aren't very healthy," said Sadia Mohsin, Ph.D., one of the study authors and a post-doctoral research scholar at San Diego State University's Heart Institute in San Diego, Cal. "We modified these biopsied stem cells and made them healthier. It is like turning back the clock so these cells can thrive again."

Modified human stem cells helped the signaling and structure of the heart cells, which were biopsied from elderly patients. Researchers modified the stem cells in the laboratory with PIM-1, a protein that promotes cell survival and growth.

Cells were rejuvenated when the modified stem cells enhanced activity of an enzyme called telomerase, which elongates telomere length. Telomeres are "caps" on the ends of chromosomes that facilitate cell replication. Aging and disease results when telomeres break off.

"There is no doubt that stem cells can be used to counter the aging process of cardiac cells caused by telomere degradation," Mohsin said.

The technique increased telomere length and activity, as well as increasing cardiac stem cell proliferation, all vital steps in combating heart failure.

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Aging Heart Cells Rejuvenated by Modified Stem Cells

New cells to replace those destroyed in diabetes type 1, cells to help heal a heart attack, cells to cure leukemia this is the promise of stem cells. Some of this is happening now; more will be available in a few years. Stem cells will usher in the era of regenerative medicine, allowing the creation of cells, tissues and organs to treat or cure diseases and injuries. This will be a fundamental alteration in our approach to medical care and a transformational medical megatrend. And it will be very personalized medicine to provide the specific individual with custom tailored new cells and tissues for organ repair or replacement. Extensive use of stem cells as therapy is still in its infancy. Call it infancy because there is so much basic science still to be understood, that it will be quite some years before we will see stem cells being used on any sort of regular basis to treat diabetes, Parkinsons disease, or heart failure after a heart attack. But time flies, many investigators are hard at work and the science may advance quickly. There are exceptions; stem cells are being actively used for a few situations and have been for many years. Among them are bone marrow or stem cell transplantation for diseases like leukemia, some cancers being treated with very high doses of chemotherapy or some individuals, especially children, with immune disorders. Since stem cells have the potential to be of ever increasing importance to medical care, albeit not for a few years, it is important to understand just what a stem cell is, generally how the various types of stem cells differ from each other and how they are either found in the body or produced in the laboratory. The key characteristics of stem cells are that 1) they can replicate themselves and 2) they can become mature cells that make up the tissue and organs of the body. Embryonic stem cells are found in the earliest divisions of the fertilized ovum and can become any of the bodys approximately 200 types of cells (liver, lung, brain) and they have the capacity when placed in tissue culture in the laboratory to divide and to replicate themselves indefinitely. We call them pluripotent in that they can become any of the various types of cells in the body. Think of them as the most fundamental cellular building block that can create the tissues and organs of our body. Adult stem cells, as the name implies, can be found in the bodies of adults (or newborns and children for that matter.) They also can self replicate but when placed in tissue culture it has not been possible to have them replicate indefinitely as embryonic stem cells do. Adult stem cells generally only can differentiate into one type of the bodys cells or tissue, i.e., are unipotent. For example muscle stem cells only become muscle cells but not liver cells. But some adult stem cells, such as those from the bone marrow, can become multiple but not all types of cells. Stem cells obtained from the umbilical cord of a newborn baby are more like adult stem cells in that they can develop into some but apparently not all cells types. In effect, they are further along in the chain of differentiation.

There are also other types of stem cells that as of now are being produced in the laboratory and which have many of the attributes of embryonic stem cells nuclear transfer, induced pluripotent, and protein-induced pluripotent stem cells, among others. To create the nuclear transfer stem cell, an unfertilized egg is obtained from a womans ovary. The egg has its nucleus extracted by a micropipette and then has the nucleus of an adult cell inserted in its place. This nucleus might be obtained from a skin cell taken from the arm of a patient with a particular problem such as diabetes. The newly created cell is placed in culture and with the appropriate signals begins to act like an embryonic stem cell in that it will divide and replicate itself and with the appropriate signals the daughter cells can become various body cell types. The hope is that these cells, genetically identical to the patient who had the skin biopsy, could be grown up into a vast number of in this example pancreatic islet cells and used to treat this individual patients diabetes.

The induced pluripotent stem cell (or iPSC) also has many of the embryonic stem cells characteristics. It is produced by taking a persons cells such as from the skin of the arm and then stimulating them by inserting a few key genes, using a retrovirus. These genes reprogram the cell to revert to what is similar to an embryonic stem cell. The concern of course is that it is induced using a virus. More recent experiments have found that certain proteins can reprogram the cell just as can the virally-inserted genes. These stem cells are known as protein-induced pluripotent stem cells (piPSC). Both are being evaluated to determine if they can be as effective as embryonic stem cells. With each of these three techniques, a clear hoped for advantage is that a person can donate his or her own cells for transformation into stem cells and from there into whatever cell is of interest, such as pancreatic islet cells that secrete insulin. Such cells transplanted back into the person would be recognized as self and not trigger rejection with a graft vs. host response by the body. This concept with each technique is therefore all about personalized medicine.

Next time I will delve more deeply into adult stem cells followed the next time by embryonic stem cells. But in the meanwhile think of stem cell science as one more of those truly transformative medical megatrends that will revolutionize the practice of medicine in the years to come and in the process improve the healthcare of you and your family.

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Medical Megatrends — Stem Cells — Part I of III