Category Archives: Stem Cells

Jan. 9, 2014 A fast and comprehensive method for determining the function of genes could greatly improve our understanding of a wide range of diseases and conditions, such as heart disease, liver disease and cancer.

The method uses stem cells with a single set of chromosomes, instead of the two sets found in most cells, to reveal what causes the "circuitry" of stem cells to be rewired as they begin the process of conversion into other cell types. The same method could also be used to understand a range of biological processes.

Embryonic stem cells rely on a particular gene circuitry to retain their original, undifferentiated state, making them self-renewing. The dismantling of this circuitry is what allows stem cells to start converting into other types of cells -- a process known as cell differentiation -- but how this happens is poorly understood.

Researchers from the University of Cambridge Wellcome Trust-MRC Stem Cell Institute have developed a technique which can pinpoint the factors which drive cell differentiation, including many that were previously unidentified. The method, outlined in the Thursday (9 January) edition of the journal Cell Stem Cell, uses stem cells with a single set of chromosomes to uncover how cell differentiation works.

Cells in mammals contain two sets of chromosomes -- one set inherited from the mother and one from the father. This can present a challenge when studying the function of genes, however: as each cell contains two copies of each gene, determining the link between a genetic change and its physical effect, or phenotype, is immensely complex.

"The conventional approach is to work gene by gene, and in the past people would have spent most of their careers looking at one mutation or one gene," said Dr Martin Leeb, who led the research, in collaboration with Professor Austin Smith. "Today, the process is a bit faster, but it's still a methodical gene by gene approach because when you have an organism with two sets of chromosomes that's really the only way you can go."

Dr Leeb used unfertilised mouse eggs to generate embryonic stem cells with a single set of chromosomes, known as haploid stem cells. These haploid cells show all of the same characteristics as stem cells with two sets of chromosomes, and retain the same full developmental potential, making them a powerful tool for determining how the genetic circuitry of mammalian development functions.

The researchers used transposons -- "jumping genes"- to make mutations in nearly all genes. The effect of a mutation can be seen immediately in haploid cells because there is no second gene copy. Additionally, since embryonic stem cells can convert into almost any cell type, the haploid stem cells can be used to investigate any number of conditions in any number of cell types. Mutations with important biological effects can then rapidly be traced to individual genes by next generation DNA sequencing.

"This is a powerful and revolutionary new tool for discovering how gene circuits operate," said Dr Leeb. "The cells and the methodology we've developed could be applied to a huge range of biological questions."

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Rewiring stem cells: New technique may revolutionize understanding of how genes function

2 hours ago This is a set of chromosomes in haploid mouse embryonic stem cells. Credit: Martin Leeb

A fast and comprehensive method for determining the function of genes could greatly improve our understanding of a wide range of diseases and conditions, such as heart disease, liver disease and cancer.

The method uses stem cells with a single set of chromosomes, instead of the two sets found in most cells, to reveal what causes the "circuitry" of stem cells to be rewired as they begin the process of conversion into other cell types. The same method could also be used to understand a range of biological processes.

Embryonic stem cells rely on a particular gene circuitry to retain their original, undifferentiated state, making them self-renewing. The dismantling of this circuitry is what allows stem cells to start converting into other types of cells - a process known as cell differentiation - but how this happens is poorly understood.

Researchers from the University of Cambridge Wellcome Trust-MRC Stem Cell Institute have developed a technique which can pinpoint the factors which drive cell differentiation, including many that were previously unidentified. The method, outlined in the Thursday (9 January) edition of the journal Cell Stem Cell, uses stem cells with a single set of chromosomes to uncover how cell differentiation works.

Cells in mammals contain two sets of chromosomes one set inherited from the mother and one from the father. This can present a challenge when studying the function of genes, however: as each cell contains two copies of each gene, determining the link between a genetic change and its physical effect, or phenotype, is immensely complex.

"The conventional approach is to work gene by gene, and in the past people would have spent most of their careers looking at one mutation or one gene," said Dr Martin Leeb, who led the research, in collaboration with Professor Austin Smith. "Today, the process is a bit faster, but it's still a methodical gene by gene approach because when you have an organism with two sets of chromosomes that's really the only way you can go."

Dr Leeb used unfertilised mouse eggs to generate embryonic stem cells with a single set of chromosomes, known as haploid stem cells. These haploid cells show all of the same characteristics as stem cells with two sets of chromosomes, and retain the same full developmental potential, making them a powerful tool for determining how the genetic circuitry of mammalian development functions.

The researchers used transposons "jumping genes" to make mutations in nearly all genes. The effect of a mutation can be seen immediately in haploid cells because there is no second gene copy. Additionally, since embryonic stem cells can convert into almost any cell type, the haploid stem cells can be used to investigate any number of conditions in any number of cell types. Mutations with important biological effects can then rapidly be traced to individual genes by next generation DNA sequencing.

"This is a powerful and revolutionary new tool for discovering how gene circuits operate," said Dr Leeb. "The cells and the methodology we've developed could be applied to a huge range of biological questions."

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Rewiring stem cells

PUBLIC RELEASE DATE:

7-Jan-2014

Contact: Jeffrey Norris jeffrey.norris@ucsf.edu 415-502-6397 University of California - San Francisco

Researchers have developed a new way to study bone disorders and bone growth, using stem cells from patients afflicted with a rare, genetic bone disease. The approach, based on Nobel-Prize winning techniques, could illuminate the illness, in which muscles and tendons progressively turn into bone, and addresses the similar destructive process that afflicts a growing number of veterans who have suffered blast injuries including traumatic amputations or injuries to the brain and nervous system. This insidious hardening of tissues also grips some patients following joint replacement or severe bone injuries.

The disease model, described in a new study by a UC San Francisco-led team, involves taking skin cells from patients with the bone disease, reprogramming them in a lab dish to their embryonic state, and deriving stem cells from them.

Once the team derived the stem cells, they identified a cellular mechanism that drives abnormal bone growth in the thus-far untreatable bone disease, called fibrodysplasia ossificans progressiva (FOP). Furthermore, they found that certain chemicals could slow abnormal bone growth in the stem cells, a discovery that might help guide future drug development.

Clinically, the genetic and trauma-caused conditions are very similar, with bone formation in muscle leading to pain and restricted movement, according to the leader of the new study, Edward Hsiao, MD, PhD, an endocrinologist who cares for patients with rare and unusual bone diseases at the UCSF Metabolic Bone Clinic in the Division of Endocrinology and Metabolism.

The human cell-based disease model is expected to lead to a better understanding of these disorders and other illnesses, Hsiao said.

"The new FOP model already has shed light on the disease process in FOP by showing that the mutated gene can affect different steps of bone formation," Hsiao said. "These different stages represent potential targets for limiting or stopping the progression of the disease, and may also be useful for blocking abnormal bone formation in other conditions besides FOP. The human stem-cell lines we developed will be useful for identifying drugs that target the bone-formation process in humans," Hsiao said.

The team's development of, and experimentation with, the human stem-cell disease model for FOP, published in the December issue of the Orphanet Journal of Rare Diseases, is a realization of the promise of research using stem cells of the type known as induced pluripotent stem (iPS) cells, immortal cells of nearly limitless potential, derived not from embryos, but from adult tissues.

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Stem cells used to model disease that causes abnormal bone growth

PUBLIC RELEASE DATE:

7-Jan-2014

Contact: Joshua Brickmann joshua.brickman@sund.ku.dk 45-51-68-04-38 University of Copenhagen

Scientists at the University of Copenhagen have gained new insight into how both early embryonic cells and embryonic stem cells are directed into becoming specialised cell types, like pancreatic and liver cells. The results have just been published in the scientific journal eLife.

This latest research from the Danish Stem Cell Center (Danstem) at the University of Copenhagen, helps identify how stem cells create so called pathways and roads supporting their own specialisation. This understanding is an important step towards stem cell-based cell therapies for conditions like diabetes and liver diseases.

"The new insight that we have gained into the impact of the physical environment on cell development is highly valuable," says Professor Joshua Brickman from DanStem, "It enables us to create the optimal physical environment in the laboratory for stem cells and progenitor cells to develop into specific, mature cells."

On the road

Developing cells constantly move and while moving around, they organise and build a physical environment very much like a small city with pathways and roads. The new research published in the scientific journal eLife shows two important things. Firstly the embryonic cells receive signals from other cells that actually instruct them in how to organise and build the road leading the cells towards early stages of pancreas and liver cells.

Professor Brickman and his team also found that they could isolate these roads from the developing stem cells and literally freeze them. The saved roads were then used in a separate experiment which showed that in the absence of an important cell signal, the road alone can be used to improve the cells' development and differentiation towards mature cells.

"Apart from gaining new important insight into cell development, our work also suggests that some of the current approaches to human embryonic stem cells specialisation towards both pancreatic and liver cells may not have been effective, because the important role of these roads, the so called extra-cellular matrix, was ignored," says Joshua Brickman.

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Stem cells on the road to specialization

Jan. 7, 2014 Scientists at the University of Copenhagen have gained new insight into how both early embryonic cells and embryonic stem cells are directed into becoming specialized cell types, like pancreatic and liver cells. The results have just been published in the scientific journal eLife.

This latest research from the Danish Stem Cell Center (Danstem) at the University of Copenhagen, helps identify how stem cells create so called pathways and roads supporting their own specialization. This understanding is an important step towards stem cell-based cell therapies for conditions like diabetes and liver diseases.

"The new insight that we have gained into the impact of the physical environment on cell development is highly valuable," says Professor Joshua Brickman from DanStem, "It enables us to create the optimal physical environment in the laboratory for stem cells and progenitor cells to develop into specific, mature cells."

Developing cells constantly move and while moving around, they organize and build a physical environment very much like a small city with pathways and roads. The new research published in the scientific journal eLife shows two important things. Firstly the embryonic cells receive signals from other cells that actually instruct them in how to organize and build the road leading the cells towards early stages of pancreas and liver cells.

Professor Brickman and his team also found that they could isolate these roads from the developing stem cells and literally freeze them. The saved roads were then used in a separate experiment which showed that in the absence of an important cell signal, the road alone can be used to improve the cells' development and differentiation towards mature cells.

"Apart from gaining new important insight into cell development, our work also suggests that some of the current approaches to human embryonic stem cells specialization towards both pancreatic and liver cells may not have been effective, because the important role of these roads, the so called extra-cellular matrix, was ignored," says Joshua Brickman.

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Stem cells on road to specialization

PUBLIC RELEASE DATE:

7-Jan-2014

Contact: David McKeon DMckeon@nyscf.org 212-365-7440 New York Stem Cell Foundation

NEW YORK, NY (January 7, 2014) Scientists at The New York Stem Cell Foundation (NYSCF) Research Institute, working in collaboration with scientists from Columbia University Medical Center (CUMC), for the first time generated induced pluripotent stem (iPS) cells lines from non-cryoprotected brain tissue of patients with Alzheimer's disease.

These new stem cell lines will allow researchers to "turn back the clock" and observe how Alzheimer's develops in the brain, potentially revealing the onset of the disease at a cellular level long before any symptoms associated with Alzheimer's are displayed. These reconstituted Alzheimer's cells will also provide a platform for drug testing on cells from patients that were definitively diagnosed with the disease. Until now, the only available method to definitively diagnose Alzheimer's disease that has been available to researchers is examining the brain of deceased patients. This discovery will permit scientists for the first time to compare "live" brain cells from Alzheimer's patients to the brain cells of other non-Alzheimer's patients.

NYSCF scientists successfully produced the iPS cells from frozen tissue samples stored for up to eleven years at the New York Brain Bank at Columbia University.

This advance, published today in Acta Neuropathologica Communications , shows that disease-specific iPS cells can be generated from readily available biobanked tissue that has not been cryoprotected, even after they have been frozen for many years. This allows for the generation of iPS cells from brains with confirmed disease pathology as well as allows access to rare patient variants that have been banked. In addition, findings made using iPS cellular models can be cross-validated in the original brain tissue used to generate the cells. The stem cell lines generated for this study included samples from patients with confirmed Alzheimer's disease and four other neurodegenerative diseases.

This important advance opens up critical new avenues of research to study cells affected by disease from patients with definitive diagnoses. This success will leverage existing biobanks to support research in a powerful new way.

iPS cells are typically generated from a skin or blood sample of a patient by turning back the clock of adult cells into pluripotent stem cells, cells that can become any cell type in the body. While valuable, iPS cells are often generated from patients without a clear diagnosis of disease and many neurodegenerative diseases, such as Alzheimer's disease, often lack specific and robust disease classification and severity grading. These diseases and their extent can only be definitively diagnosed by post-mortem brain examinations. For the first time we will now be able to compare cells from living people to cells of patients with definitive diagnoses generated from their banked brain tissue.

Brain bank networks, which combined contain tens of thousands of samples, provide a large and immediate source of tissue including rare disease samples and a conclusive spectrum of disease severity among samples. The challenge to this approach is that the majority of biobanked brain tissue was not meant for growing live cells, and thus was not frozen in the presence of cryoprotectants normally used to protect cells while frozen. NYSCF scientists in collaboration with CUMC scientists have shown that these thousands of samples can now be used to make living human cells for use in disease studies and to develop new drugs or preventative treatments for future patients.

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NYSCF scientists make living brain cells from Alzheimer's patients biobanked brain tissue

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Newswise With the help of biomimetic matrices, a research team led by bioengineers at the University of California, San Diego has discovered exactly how calcium phosphate can coax stem cells to become bone-building cells. This work is published in the Proceedings of the National Academy of Sciences the week of Jan. 6, 2014.

UC San Diego Jacobs School of Engineering professor Shyni Varghese and colleagues have traced a surprising pathway from these biomaterials to bone formation. Their findings will help them refine the design of biomaterials that encourage stem cells to give rise to new bone. The researchers say their study may also point out new targets for treating bone defects and bone metabolic disorders such as major fractures and osteoporosis.

The materials are built to mimic the bodys own cellular niches, in which undifferentiated or blank-slate stem cells from bone marrow transform into specific bone-forming cells. We knew for years that calcium phosphate-based materials promote osteogenic differentiation of stem cells, but none of us knew why, Varghese said.

As engineers, we want to build something that is reproducible and consistent, she explained, so we need to know how building factors contribute to this end.

The researchers found that when phosphate ions gradually dissolve from these materials, they are taken up by the stem cells and used for the production of ATP, a key metabolic molecule. An ATP metabolic product called adenosine then signals the stem cells to commit to becoming bone-forming cells.

Varghese said it was a surprise to her team that the biomaterials were connected to metabolic pathways. And we didnt know how these metabolic pathways could influence stem cells commitment to bone formation.

While the PNAS findings only apply to bone building, Varghese and her students at UC San Diego are working on a variety of projects to understand how stem cells thrive and differentiate into a variety of cell types. With this information, they hope to design biomaterials that can be used to help transform stem cells into tissues that may someday replace diseased or degenerated bone, muscle, or blood vessels.

Stem cell research may seem like an unusual endeavor for engineers, but tissue construction and the development of biomaterials have become one more type of building in the engineering repertoire, Varghese said.

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Biomaterials Get Stem Cells to Commit to a Bony Future

PUBLIC RELEASE DATE:

6-Jan-2014

Contact: Sandy Van sandy@prpacific.com 808-526-1708 Cedars-Sinai Medical Center

LOS ANGELES (Jan. 6, 2014) Researchers at the Cedars-Sinai Maxine Dunitz Neurosurgical Institute and Department of Neurosurgery identified immune system targets on cancer stem cells cells from which malignant brain tumors are believed to originate and regenerate and created an experimental vaccine to attack them.

Results of laboratory and animal studies are published in the online edition of Stem Cells Translational Medicine, and will appear in the March 2014 print edition. A Phase I safety study in human volunteers with recurrent glioblastoma multiforme, the most common and aggressive brain tumor in adults, is underway.

Like normal stem cells, cancer stem cells have the ability to self-renew and generate new cells, but instead of producing healthy cells, they create cancer cells. In theory, if the cancer stem cells can be destroyed, a tumor may not be able to sustain itself, but if the cancer originators are not removed or destroyed, a tumor will continue to return despite the use of existing cancer-killing therapies.

The researchers identified certain fragments of a protein CD133 that is found on cancer stem cells of some brain tumors and other cancers. In the laboratory, they cultured the proteins with dendritic cells, the immune system's most powerful antigen-presenting cells, which are responsible for helping the immune system recognize and attack invaders.

Studies in lab mice showed that the resulting vaccine was able to stimulate an immune response against the CD133 proteins without causing side effects such as an autoimmune reaction against normal cells or organs.

"CD133 is one of several proteins made at high levels in the cancer stem cells of glioblastoma multiforme. Because this protein appears to be associated with resistance of the cancer stem cells to treatment with radiation or chemotherapy or both, we see it as an ideal target for immunotherapy. We have found at least two fragments of the protein that can be targeted to trigger an immune response to kill tumor cells. We don't know yet if the response would be strong enough to prevent a tumor from coming back, but we now have a human clinical trial underway to assess safety for further study," said John Yu, MD, vice chair of the Department of Neurosurgery, director of surgical neuro-oncology, medical director of the Brain Tumor Center and neurosurgical director of the Gamma Knife Program at Cedars-Sinai. He is senior author of the journal article.

With standard care, which includes surgery, radiation treatment and chemotherapy, median length of survival is 15 months for patients diagnosed with glioblastoma multiforme. Cedars-Sinai researchers have studied dendritic cell immunotherapy since 1997, with the first patient human clinical trial launched in 1998.

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Cedars-Sinai researchers target cancer stem cells in malignant brain tumors

Stanford Report, January 6, 2014

Irving Weissman, director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford.

The Stanford University School of Medicine has received $90 million from Ludwig Cancer Research on behalf of its founder, Daniel K. Ludwig, to support the school's innovative work in cancer stem cells, which are believed to drive the growth of many cancers.

Stanford is one of six institutions to share in Ludwig's $540 million contribution to the field of cancer research. Announced today, the gift is one of the largest ever made to the field from an individual donor.

The funding will augment the existing endowment for the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, established in 2006, where scientists already have discovered some promising therapies that are moving into clinical trials.

"The gift from Ludwig Cancer Research is truly historic," said Stanford President John Hennessy. "Over the years, Ludwig has been a generous supporter of cancer research, and through its support changed the course of cancer treatment. But this extraordinary gift will spur innovation well into the future.Stanford is distinguished for its cancer research and has assembled a 'dream team' of dedicated scientists at the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. This gift is a tremendous vote of confidence in the work they and their colleagues at other Ludwig Centers are doing and will provide essential support as they pioneer new treatments and therapies."

The Ludwig gift will complement Stanford's Cancer Initiative, a $250 million effort to advance research and improve patient care, said Lloyd Minor, dean of the Stanford School of Medicine.

"We are very grateful to Ludwig Cancer Research for this exceptional gift, which will provide momentum for further discoveries in cancer stem cells and spur the development of new therapies," Minor said. "Together with our Cancer Initiative, it represents an opportunity to truly transform cancer research and treatment."

With his latest gift, Ludwig has now committed $150 million to Stanford. The university's Ludwig Center, the only cancer stem cell center of its kind, is directed by Irving Weissman, the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research at Stanford.

The first evidence of cancer stem cells was found in acute myeloid leukemia in 1994 by Canadian scientist John Dick. Weissman and his colleagues purified human blood-forming stem cells in 1992 and human leukemia stem cells in 2000 and later identified potential therapeutic targets on them. Since then, Michael Clarke, professor of medicine at Stanford and a Ludwig Center deputy director, isolated cancer stem cells in breast cancer, pancreatic cancers and colorectal cancer, and with Weissman head and neck cancers, bladder cancer, myelomas and other cancers.

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Stanford shares in $540 million gift from Ludwig Cancer Research

Current ratings for: Stem cell transplantation: new approach 'protects from rejection'

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Many patients who undergo stem cell transplantations run the risk that their immune system may reject the donor cells. But new research from the University of California-San Diego has detailed a new approach that may help tackle this problem. This is according to a study published in the journal Cell Stem Cell.

The research team, led by Yang Xu, says their findings may also provide researchers with a better understanding as to how tumors avert the immune system as they spread throughout the human body.

In collaboration with researchers from China, the investigators created "humanized" laboratory mice.

The mice had a functional human immune system that was able to effectively reject a large number of foreign cells that originated from human embryonic stem cells.

The researchers explain that since human embryonic stem cells are "allogenic," meaning they differ from the body's own cells, a healthy human immune system will naturally attack the stem cells.

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Stem cell transplantation: new approach 'protects from rejection'