Stem cell progeny tell their parents when to turn on

May 09, 2014 A signal from Transit-Amplifying Cells (TACs) activates stem cells in the hair follicle, researchers have found. Both types of cells appear in green (top), with TACs clustered lower down. The researchers identified the signal as Sonic Hedgehog. In experiments, such as this one (bottom), they disabled the signal, interfering with hair growth and regeneration.

(Phys.org) Stem cells switch off and on, sometimes dividing to produce progeny cells and sometimes resting. But scientists don't fully understand what causes the cells to toggle between active and quiet states.

New research in Elaine Fuchs' Laboratory of Mammalian Cell Biology and Development focused on stem cells in the hair follicle to determine what switches them on. The researchers found cells produced by the stem cells, progeny known at Transit-Amplifying Cells or TACs, emit a signal that tells quiet hair follicle stem cells to become active.

"Many types of mammalian stem cells produce TACs, which act as an intermediate between the stem cells and their final product: fully differentiated cells in blood, skin and elsewhere," says Ya-Chieh Hsu, who conducted the research while as a postdoc in the lab and will soon move to Harvard University. "In the past, TACs were seen as a population of cells that sat by passively cranking out tissues. No one expected them to play a regulatory role."

Hsu and Fuchs went a step further to identify the signal sent out by the TACs. They pinpointed a cell-division promoting protein called Sonic Hedgehog, which plays a role in the embryonic development of the brain, eyes and limbs.

Stem cells are medically valuable because they have the potential to produce a number of specialized cells suitable for specific roles. Stem cells' production of these differentiated cells is crucial to normal maintenance, growth and repair. Many tissues have two populations of stem cells: one that divides rarely, known as the quiescent stem cells, and another that is more prone to proliferate, known as primed stem cells. Regardless of their proliferation frequency, most stem cells in humans do not directly produce differentiated progeny cells; instead, they give rise to an intermediate proliferating population, the TACs.

The hair follicle, the tiny organ that produces a hair, forms a narrow cavity down into the skin. It cycles between rounds of growth, destruction and rest. When entering the growth phase, the primed stem cell population is always the first to divide and generates the TACs clustered lower down in the hair follicle. Primed stem cell proliferation sets the stage for the next round of hair growth, a process which ensures hairs are replaced as they are lost over time. Proliferating TACs produce the hair shaft, as well as all the cells surrounding the hair underneath the skin, which make up the follicle itself.

At the outset, Hsu and Fuchs suspected a role for both the TACs and for Sonic Hedgehog in hair regeneration.

"We noticed that the primed stem cell population gets activated early and makes the TACs, while the quiescent stem cell population only becomes activated once TACs are generated. This correlation prompted us to look for a signal that is made by the TACs. Sonic Hedgehog is that signal, as we went on to demonstrate," explained Fuchs.

In experiments described this week in Cell, Hsu disabled TACs' ability to produce the Sonic Hedgehog protein by knocking out the gene responsible in the hair follicles of adult mice. As a result, the proliferation of hair follicle stem cells and their TACs are both compromised. They further showed that it is the quiescent stem cell population which requires Sonic Hedgehog directly for proliferation.

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Stem cell progeny tell their parents when to turn on

Scientists Decode Epigenetic Mechanisms Distinguishing Stem Cell Function and Blood Cancer

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Newswise (Lebanon, NH, 5/8/14) Researchers at Dartmouths Norris Cotton Cancer Center have published results from a study Cell Reports that discovers a new mechanism that distinguishes normal blood stem cells from blood cancers.

These findings constitute a significant advance toward the goal of killing leukemia cells without harming the bodys normal blood stem cells which are often damaged by chemotherapy, said Patricia Ernst, PhD, co-director of the Cancer Mechanisms Program of the Norris Cotton Cancer Center and an associate professor in Genetics at Geisel School of Medicine.

The study focused on a pathway regulated by a gene called MLL1 (for Mixed Lineage Leukemia). Ernst served as principal investigator; Bibhu Mishra, PhD, as lead author.

When the MLL1 gene is damaged, it can cause leukemia, which is a cancer of the blood, often occurring in very young patients. Researchers found that the normal version of the gene controls many other genes in a manner that maintains the production of blood cells.

This control becomes chaotic when the gene is damaged or broken and that causes the normal blood cells to turn into leukemia, said Ernst.

The researchers showed that the normal gene acts with a partner gene called MOF that adds small acetyl chemical modification around the genes that it controls. The acetyl modification acts as a switch to turn genes on. When this function is disrupted, MLL1 cannot maintain normal blood stem cells.

The researchers also found that a gene called Sirtuin1 (more commonly known for controlling longevity) works against MLL1 to keep the proper amount of acetyl modifications on important stem cell genes. Blood cancers involving MLL1, in contrast, do not have this MOF-Sirtuin balance and place a different chemical modification on genes that result in leukemia.

Blood stem cells also represent an important therapy for patients whose own stem cells are destroyed by chemotherapy. This study also reveals a new way to treat blood stem cells from donors that would expand their numbers.

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Scientists Decode Epigenetic Mechanisms Distinguishing Stem Cell Function and Blood Cancer

Study Urges Caution in Stem Cell Clinical Trials for Heart Attack Patients

CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER. (PRNewsFoto/Cincinnati Children's Hospital Medical Center)

CINCINNATI, May 7, 2014 /PRNewswire-USNewswire/ --A new study in Nature challenges research data that form the scientific basis of clinical trials in which heart attack patients are injected with stem cells to try and regenerate damaged heart tissue.

Researchers at Cincinnati Children's Hospital Medical Center and the Howard Hughes Medical Institute (HHMI), report May 7 that cardiac stem cells used in ongoing clinical trials which express a protein marker called c-kit do not regenerate contractile heart muscle cells at high enough rates to justify their use for treatment.

Including collaboration from researchers at Cedars-Sinai Heart Institute in Los Angeles and the University of Minnesota's Lillehei Heart Institute, the study uncovers new evidence in what has become a contentious debate in the field of cardiac regeneration, according to Jeffery Molkentin, PhD, study principal investigator and a cardiovascular molecular biologist and HHMI investigator at the Cincinnati Children's Heart Institute.

"Our data suggest any potential benefit from injecting c-kit-positive cells into the hearts of patients is not because they generate new contractile cells called cardiomyocytes," Molkentin said. "Caution is warranted in further clinical testing of this method until the mechanisms in play here are better defined or we are able to dramatically enhance the potential of these cells to generate cardiomyocytes."

Numerous heart attack patients have already been treated with c-kit-positive stem cells that are removed from healthy regions of a damaged heart then processed in a laboratory, Molkentin explained. After processing, the cells are then injected into these patients' hearts. The experimental treatment is based largely on preclinical studies in rats and mice suggesting that c-kit-positive stem cells completely regenerate myocardial cells and heart muscle. Thousands of patients have also previously undergone a similar procedure for their hearts but with bone marrow stem cells.

Molkentin and his colleagues report those previous preclinical studies in rodents do not reflect what really occurs within the heart after injury, where internal regenerative capacity is almost non-existent. Molkentin also said that combined data from multiple clinical trials testing this type of treatment show most patients experienced a roughly 3-5 percent improvement in heart ejection fraction a measurement of how forcefully the heart pumps blood. Data in the current Nature study suggest this small benefit may come from the ability of c-kit-positive stem cells in heart to cause the growth of capillaries, which improves circulation within the organ, but not by generating new cardiomyocytes.

"What we show in our study is that c-kit-positive stem cells from the heart like to make endothelial cells that form capillaries. But in their natural environment in the heart, these c-kit positive cells do not like to make cardiomyocytes," Molkentin said. "They will produce cardiomyocytes, but at rates so low roughly one in every 3,000 cells it becomes meaningless."

The c-kit protein is expressed on the surface of progenitor cells originally identified in bone marrow. These c-kit expressing cells can generate multiple different cell types that are destined to help form specific organ tissues or other parts of the body. Given its presence in bone marrow, c-kit cells are also involved in the production of different types of immune system cells.

Researchers in the current study worked with two lines of genetically bred mice to see how efficiently c-kit-positive cardiac progenitor cells would regenerate cardiomyocytes in the hearts of the animals. The authors measured heart cell regeneration rates during the animals' embryonic development, during aging and after myocardial infarction (heart attack).

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Study Urges Caution in Stem Cell Clinical Trials for Heart Attack Patients

Molecular Biology Chair Eric Olson to Head to New Hamon Center for Regenerative Medicine

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Newswise DALLAS May 7, 2014 UT Southwestern Medical Center today announced the formation of the Hamon Center for Regenerative Science and Medicine led by Dr. Eric Olson, Chairman of the Department of Molecular Biology.

This new Center was made possible by a $10 million endowment gift from the Hamon Charitable Foundation. It is being established to promote discoveries that will provide new approaches to healing and regeneration, including advances in stem cell biology, tissue engineering, and organ fabrication.

We look forward to the emergence of the Hamon Center as a leading source of transformative insights into regenerative science and medicine, said Dr. Daniel K. Podolsky, President of UT Southwestern. We are delighted to be able to announce this very generous gift from the Hamon Foundation, the establishment of the Hamon Center for Regenerative Science and Medicine, and this important new role for Dr. Olson.

Dr. Olsons work has produced new insights into heart development and regeneration. His work has illuminated a detailed genetic model for heart development that provides a framework for how these genes function in normal and abnormal heart development. These advances provide a basis for the development of new approaches to the treatment and prevention of cardiac defects in infants and cardiac repair in adults, including several therapeutics already in development.

We all know what degeneration is. Thats what happens with age. Regeneration is the opposite. It centers on how to rejuvenate aged and diseased tissues, said Dr. Olson. The goal of this Center is to understand the basic mechanisms for tissue and organ formation, and then to use that knowledge to regenerate, repair, and replace tissues damaged by aging and injury.

Under Dr. Olsons leadership, the Hamon Center will both foster collaborative interactions among existing faculty and, with its appointing authority, recruit junior and senior new faculty. In addition, the Center will support new core facilities, expanded biobank activities, and the development of new training and educational activities related to regenerative science and medicine.

Dr. Olsons work has been widely recognized by numerous awards and honors, including his election to the National Academy of Sciences, the Institute of Medicine, and the American Academy of Arts and Sciences. More recently, he received the Passano Award in 2012, the Research Achievement Award from the International Society for Heart Research in 2013, and also in 2013, the March of Dimes Prize in Developmental Biology.

Dr. Olson has been a member of the UTSouthwestern community since he was recruited in 1995 to be the founding Chair of the Department of Molecular Biology. He holds the Annie and Willie Nelson Professorship in Stem Cell Research, the Pogue Distinguished Chair in Research on Cardiac Birth Defects, and the Robert A. Welch Distinguished Chair in Science.

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Molecular Biology Chair Eric Olson to Head to New Hamon Center for Regenerative Medicine

Accusations pile up amid Japans stem-cell controversy

The Asahi Shimbun via Getty Images

The investigative committee that said a RIKEN scientist had committed misconduct, presenting its findings on 1 April in Tokyo. From left to right: Shunsuke Ishii, Atsushi Iwama, Haruhiko Koseki, Yoichi Shinkai, Tetsuya Taga and Jun Watanabe

Four of the six members of a Japanese committee that found misconduct in studies claiming to demonstrate a simple technique to produce stem cells are now facing allegations of irregularities in their own published work.

The allegations complicate an already murky controversy over the technology, known as stimulus-triggered acquisition of pluripotency (STAP). Stem-cell biologist Haruko Obokata of the RIKEN Center for Developmental Biology in Kobe, Japan, described in two Nature papers published on 30 January1, 2 how she and her colleagues had reprogrammed mouse cells into stem cells by soaking them in acid or applying physical pressure.

Within weeks, numerous problems with the papers surfaced, including manipulated and duplicated images. On 1 April Obokata was charged with misconduct by a RIKEN investigative committee comprising five scientists and a lawyer. Obokata appealed the judgement on 8 April, and the committee was given 50 days to consider that appeal. On 6 May, the Japanese media reported that the investigative committee decided to deny Obokata's request for a re-examination. Obokata can no longer appeal the finding through the organization's appeal system. RIKEN will now begin the process of deciding penalties to Obokata and her co-authors.

On 25 April, the head of the investigation committee, Shunsuke Ishii, resigned from the committee after manipulated images from two of his earlier papers were posted on the Internet. Ishii maintains that neither of the problems amount to fraud, and he posted photos from the original laboratory notebooks to support that point. RIKEN launched a preliminary inquiry into his papers.

More trouble arose for RIKEN on 30 April, when a whistle-blower alleged problems in the images of papers co-authored by two other RIKEN researchers on the committee, Haruhiko Koseki and Yoichi Shinkai. RIKEN launched a preliminary investigation into the allegations that same day. Satoru Kagaya, a RIKEN spokesman, says that the whistle-blower, whose name RIKEN will not reveal, alleges that four papers from Koseki, published between 2003 and 2011, and one paper by Shinkai, published in 2005, contain data that were manipulated in one or two spots.

Meanwhile, also on 30 April, a journalist from the daily newspaper Asahi Shimbun notified Tokyo Medical and Dental University of allegations regarding Tetsuya Taga, the university's president and another one of the RIKEN panel investigators. Two papers on neural stem cells co-authored by Taga, from 2004 and 2005, each had two illustrations that, the journalist said, appeared to be manipulations.

The next day, the university launched a preliminary enquiry headed by four university administrators. After one day of deliberation, which included a discussion with Taga and two co-authors and an examination of laboratory notebooks, the university concluded that Taga was not guilty of misconduct. A university spokesperson declined to say whether the university found no manipulations at all or whether they found manipulations but deemed them not to be misconduct. The spokesperson said a clarification of that issue will be posted online tomorrow.

Obokatas lawyer has stated that the problems in the committee members' papers are akin to those found in Obokatas errors, but not fraud.

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Accusations pile up amid Japans stem-cell controversy

FDAs Adult Stem Cell Research

Scientists who are part of the Food and Drug Administrations MSC Consortium, are studying adult mesenchymal stem cells (MSCs) that could eventually be used to repair, replace, restore or regenerate cells in the body, including those needed for heart and bone repair.

According to the FDA, theinvestigational work is unprecedented: Seven labs at FDA's Center for Biologics Evaluation and Research formed the consortium to fill in gaps in knowledge about how stem cells function.

A consumer update from FDA quotes Carolyn A. Wilson, Ph.D., associate director for research at the center, as saying, This research aims to facilitate development of this important class of innovative medical products. Its the first time weve done anything like this, and its proven to be a very useful approach. Its worked so well because this is a huge, complicated project that requires expertise in many different technologies and methods.

The research could ultimately be key to the advancement of personalized medicine, the practice in which medical treatment is tailored to the needs of an individual patient.Its not science fiction,says Steven R. Bauer, Ph.D., chief of the Cellular and Tissue Therapy Branch in FDAs Office of Cellular Tissue and Gene Therapies.For me, regenerative medicine is the most exciting part of what we regulate in our office.

Visit FDAs Consumer Updates page for more information on adult sem cells and regenerative medicine.

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What are Stem Cells? | UNMC

What are Stem Cells?

Types of Stem Cells

Why are Stem Cells Important?

Can doctors use stem cells to treat patients?

Pros and Cons of Using Stem Cells

What are Stem Cells?

There are several different types of stem cells produced and maintained in our system throughout life. Depending on the circumstances and life cycle stages, these cells have different properties and functions. There are even stem cells that have been created in the laboratory that can help us learn more about how stem cells differentiate and function. A few key things to remember about stem cells before we venture into more detail:

Stem cells are the foundation cells for every organ and tissue in our bodies. The highly specialized cells that make up these tissues originally came from an initial pool of stem cells formed shortly after fertilization. Throughout our lives, we continue to rely on stem cells to replace injured tissues and cells that are lost every day, such as those in our skin, hair, blood and the lining of our gut.

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Stem Cell History

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What are Stem Cells? | UNMC

Nuclear transfer to reprogram adult patient cells into stem cells demonstrated

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The capacity to reprogram adult patient cells into pluripotent, embryonic-like, stem cells by nuclear transfer has been reported as a breakthrough by scientists from the US and the Hebrew University of Jerusalem.

The work, described in the journal Nature, was accomplished by researchers from the New York Stem Cell Foundation Research Institute and Columbia University and by Nissim Benvenisty, the Herbert Cohn professor of Cancer Research and director of the Stem Cell Unit at the Institute of Life Sciences at the Hebrew University of Jerusalem, and his graduate student Ido Sagi. The latter assisted in the characterization of the pluripotent nature of these cells.

Pluripotency means the ability of stem cells to develop into all the cells of our body, including those in the brain, heart, liver and blood. In 2012, the Nobel Prize in Physiology or Medicine was awarded for two discoveries showing that mature (differentiated) cells can be converted into pluripotent, embryonic-like cells, either by forced expression of genetic factors or by transfer of cell nuclei into female eggs, in a process called "reprogramming."

However, the actual ability to reprogram cells from humans by nuclear transfer had only been accomplished until now by using fetal cells for this purpose, until this latest work involving reprogramming of adult patient cells demonstrated by the researchers from the US and the Hebrew University, as described in the new Nature article.

Future research should allow further characterization of these novel, pluripotent cell types and their comparison to other stem cells. "Human pluripotent stem cells generated from adult cells may change the face of medicine," says Prof. Benvenisty, leading to totally new, personalized genetic therapy involving the reprograming of a patient's own cells to achieve cell replacement and healing.

Explore further: Soft substrates may promote the production of induced pluripotent stem cells

More information: "Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells." Mitsutoshi Yamada, et al. Nature (2014) DOI: 10.1038/nature13287. Received 04 February 2014 Accepted 27 March 2014 Published online 28 April 2014

Converting adult cells into stem cells that can develop into other types of specialized cells is one of the most active areas of medical research, holding great promise for the treatment of disease and repair ...

For the first time, US researchers have cloned embryonic stem cells from adult cells, a breakthrough on the path towards helping doctors treat a host of diseases. ...

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Nuclear transfer to reprogram adult patient cells into stem cells demonstrated

A transcription factor called SLUG helps determines type of breast cancer

PUBLIC RELEASE DATE:

2-May-2014

Contact: Siobhan Gallagher siobhan.gallagher@tufts.edu 617-636-6586 Tufts University, Health Sciences Campus

Findings and Significance: During breast-tissue development, a transcription factor called SLUG plays a role in regulating stem cell function and determines whether breast cells will mature into luminal or basal cells.

Studying factors, such as SLUG, that regulate stem-cell activity and breast-cell identity are important for understanding how breast tumors arise and develop into different subtypes. Ultimately, this knowledge may help the development of novel therapies targeted to specific breast-tumor subtypes.

Background: Stem cells are immature cells that can differentiate, or develop, into different cell types. Stem cells are important for replenishing cells in many tissues throughout the body. Defects that affect stem-cell activity can lead to cancer because mutations in these cells can cause uncontrollable growth. Some transcription factors regulate the differentiation or "programming" of breast stem cells into the more mature cells of the breast tissue. Abnormal expression of these transcription factors can change the normal programming of cells, which can lead to imbalances in cell types and the over-production of cells with enhanced properties of stem cells.

Breast tissue has two main types of cells: luminal cells and basal cells. Transcription factors, like SLUG, help control whether cells are programmed to become luminal cells or basal cells during normal breast development. In cancer, transcription factors can become deregulated, influencing what type of breast tumor will form. In aggressive basal-type breast tumors, SLUG is often over-expressed.

Previous work led by Charlotte Kuperwasser, principal investigator and senior author, determined that some common forms of breast cancer originate from luminal cells, whereas rare forms of breast cancer originate from basal cells. This difference in origins suggests that genes that affect the ability of a cell to become luminal or basal may also affect the formation of breast tumors. Because SLUG can regulate breast-cell differentiation, Kuperwasser's team investigated SLUG's role in breast-cell differentiation and tumor growth.

How the Study Was Conducted: The research team reduced the expression of the SLUG gene in human-derived breast cells and then used cell-sorting techniques to separate the cells into groups of luminal, basal, and stem cells. Next, they used mathematical modeling to measure the rate and frequency that each of the three cell types changed into another cell type. By comparing the rates between control cells and cells in which SLUG was reduced, the team was able to determine the role of SLUG in luminal-, basal-, and stem-cell transitions.

To test the result of their mathematical model, the research team examined and compared breast-tissue samples from mice in two groups: a control group with normal SLUG and an experimental group that did not express SLUG. Mammary glands from the experimental and control groups were analyzed for changes in structure, the amount and distribution of luminal and basal cells in the gland, and whether these cells had stem-cell activity.

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A transcription factor called SLUG helps determines type of breast cancer

Stem cells from some infertile men form germ cells when transplanted into mice, study finds

PUBLIC RELEASE DATE:

1-May-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center

STANFORD, Calif. Stem cells made from the skin of adult, infertile men yield primordial germ cells cells that normally become sperm when transplanted into the reproductive system of mice, according to researchers at the Stanford University School of Medicine and Montana State University.

The infertile men in the study each had a type of genetic mutation that prevented them from making mature sperm a condition called azoospermia. The research suggests that the men with azoospermia may have had germ cells at some point in their early lives, but lost them as they matured to adulthood.

Although the researchers were able to create primordial germ cells from the infertile men, their stem cells made far fewer of these sperm progenitors than did stem cells from men without the mutations. The research provides a useful, much-needed model to study the earliest steps of human reproduction.

"We saw better germ-cell differentiation in this transplantation model than we've ever seen," said Renee Reijo Pera, PhD, former director of Stanford's Center for Human Embryonic Stem Cell Research and Education. "We were amazed by the efficiency. Our dream is to use this model to make a genetic map of human germ-cell differentiation, including some of the very earliest stages."

Unlike many other cellular and physiological processes, human reproduction varies in significant ways from that of common laboratory animals like mice or fruit flies. Furthermore, many key steps, like the development and migration of primordial germ cells to the gonads, happen within days or weeks of conception. These challenges have made the process difficult to study.

Reijo Pera, who is now a professor of cell biology and neurosciences at Montana State University, is the senior author of a paper describing the research, which will be published May 1 in Cell Reports. The experiments in the study were conducted at Stanford, and Stanford postdoctoral scholar Cyril Ramathal, PhD, is the lead author of the paper.

The research used skin samples from five men to create what are known as induced pluripotent stem cells, which closely resemble embryonic stem cells in their ability to become nearly any tissue in the body. Three of the men carried a type of mutation on their Y chromosome known to prevent the production of sperm; the other two were fertile.

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Stem cells from some infertile men form germ cells when transplanted into mice, study finds