Astrocytes: Human Brain's Most Ubiquitous Cell Cultivated in Lab Dish

Pity the lowly astrocyte, the most common cell in the human nervous system
Sunday, 22 May 2011

Long considered to be little more than putty in the brain and spinal cord, the star-shaped astrocyte has found new respect among neuroscientists who have begun to recognize its many functions in the brain, not to mention its role in a range of disorders of the central nervous system.



Prof. Su-Chun Zhang.

Now, writing in the current (May 22) issue of the journal Nature Biotechnology, a group led by University of Wisconsin-Madison stem cell researcher Su-Chun Zhang reports it has been able to direct embryonic and induced human stem cells to become astrocytes in the lab dish.
The ability to make large, uniform batches of astrocytes, explains Zhang, opens a new avenue to more fully understanding the functional roles of the brain's most commonplace cell, as well as its involvement in a host of central nervous system disorders ranging from headaches to dementia. What's more, the ability to culture the cells gives researchers a powerful tool to devise new therapies and drugs for neurological disorders.

"Not a lot of attention has been paid to these cells because human astrocytes have been hard to get," says Zhang, a researcher at UW-Madison's Waisman Center and a professor of neuroscience in the UW-Madison School of Medicine and Public Health.

"But we can make billions or trillions of them from a single stem cell."

Astrocytes are star-shaped cells that are

the most common cell in the human brain

and have now been grown from embryonic

and induced stem cells in the laboratory

of UW-Madison neuroscientist

Su-Chun Zhang. Once considered mere

putty or glue in the brain, astrocytes

are of growing interest to biomedical

research as they appear to play key

roles in many of the brain's basic functions,

as well as neurological disorders ranging

from headaches to dementia. In this

picture astrocyte progenitors and immature

astrocytes cluster to form an "astrosphere."

The work was conducted at UW-Madison's

Waisman Center. Credit: Photo provided

by Robert Krencik/ UW-Madison.

Although astrocytes have gotten short shrift from science compared to neurons, the large filamentous cells that process and transmit information, scientists are turning their attention to the more common cells, as their roles in the brain become better understood. There are a variety of astrocyte cell types and they perform such basic housekeeping tasks as helping to regulate blood flow, soaking up excess chemicals produced by interacting neurons and controlling the blood-brain barrier, a protective filter that keeps dangerous molecules from entering the brain.

Astrocytes, some studies suggest, may even play a role in human intelligence given that their volume is much greater in the human brain than any other species of animal.

"Without the astrocyte, neurons can't function," Zhang notes.

"Astrocytes wrap around nerve cells to protect them and keep them healthy. They participate in virtually every function or disorder of the brain."

The ability to forge astrocytes in the lab has several potential practical outcomes, according to Zhang. They could be used as screens to identify new drugs for treating diseases of the brain, they can be used to model disease in the lab dish and, in the more distant future, it may be possible to transplant the cells to treat a variety of neurological conditions, including brain trauma, Parkinson's disease and spinal cord injury. It is possible that astrocytes prepared for clinical use could be among the first cells transplanted to intervene in a neurological condition as the motor neurons affected by the fatal amyotrophic lateral sclerosis, also known as Lou Gehrig's disease, are swathed in astrocytes.

"With an injury or neurological condition, neurons in the brain have to work harder, and doing so they make more neurotransmitters," chemicals that in excess can be toxic to other cells in the brain, Zhang says.

"One idea is that it may be possible to rescue motor neurons by putting normal, healthy astrocytes in the brain," according to Zhang.

"These cells are really useful as a therapeutic target."

The technology developed by the Wisconsin group lays a foundation to make all the different species of astrocytes. What's more, it is possible to genetically engineer them to mimic disease so that previously inaccessible neurological conditions can be studied in the lab.

Source: University of Wisconsin-Madison
Contact: Contact: Su-Chun Zhang

Reference:
Specification of transplantable astroglial subtypes from human pluripotent stem cells
Robert Krencik, Jason P Weick, Yan Liu, Zhi-Jian Zhang & Su-Chun Zhang
Nature Biotechnology, 22 May 2011, doi:10.1038/nbt.1877
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Predicting the Fate of Personalized Cells Next Step toward New Therapies

Predicting the Fate of Personalized Cells Next Step toward New Therapies
Thursday, 19 May 2011


Kenneth S. Zaret, PhD.

Discovering the step-by-step details of the path embryonic cells take to develop into their final tissue type is the clinical goal of many stem cell biologists. To that end Kenneth S. Zaret, PhD, of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania, and associate director of the Penn Institute for Regenerative Medicine, and Cheng-Ran Xu, PhD, a postdoctoral researcher in the Zaret laboratory, looked at immature cells called progenitors and found a way to potentially predict their fate. They base this on how the protein spools around which DNA winds — called histones — are marked by other proteins. This study appeared this week in Science.
In the past, researchers grew progenitor cells and waited to see what they differentiated into. Now, they aim to use this marker system, outside of a cell's DNA and genes, to predict the eventual fate. This extra-DNA system of gene expression control is called epigenetics.

"We were surprised that there's a difference in the epigenetic marks in the process for liver versus pancreas before the cell-fate 'decision' is made." says Zaret.

"This suggests that we could manipulate the marks to influence fate or look at marks to better guess the fate of cells early in the differentiation process."

"How cells become committed to particular fates is a fundamental question in developmental biology," said Susan Haynes, PhD, program director in the Division of Genetics and Developmental Biology at the National Institutes of Health, which funds this line of research.

"This work provides important new insights into the early steps of this process and suggests new approaches for controlling stem-cell fate in regenerative medicine therapies."

A Guiding Path
How the developing embryo starts to apportion different functions to different cell types is a key question for developmental biology and regenerative medicine. Guidance along the correct path is provided by regulatory proteins that attach to chromosomes, marking part of the genome to be turned on or off. But first the two meters of tightly coiled DNA inside the nucleus of every cell must be loosened a bit. Regulatory proteins help with this, exposing a small domain near the target gene.

Earliest cells that form the liver (blue)

emerging from progenitor cells (yellow)

in the early embryo (green). Credit: Ken

Zaret, PhD, Perelman School of Medicine

at the University of Pennsylvania.

Chemical signals from neighbouring cells in the embryo tell early progenitor cells to activate genes encoding proteins. These, in turn, guide the cells to become liver or pancreas cells, in the case of Zaret's work. Over several years, his lab has unveiled a network of the common signals in the mouse embryo that govern development of these specific cell types.

Zaret likens the complexity of this system to the 26-letter alphabet being able to encode Shakespeare or a menu at a restaurant. Many investigators are now trying to broadly reprogram cells into desired cell fates for potential therapeutic uses.

The researchers had previously shown that a particular growth factor that attaches to the cell surface, gives a specific chemical signal for cell-type fate, promoting development along the liver-cell path and suppressing development along the pancreas-cell path. Liver and pancreas cells originate from a common progenitor cell type.

Zaret's group figured out which enzymes — called histone acetyl transferases or methyl transferases (that add methyl groups or acetyl groups to histones) are relevant to the pancreas arm of the liver-pancreas fate decision. They used mice in which they knocked out the function for one enzyme type versus the other to induce the development of fewer liver cells and more pancreas cells.

The transferases mark genes for liver and pancreas fates differently before a cell moves into the next intermediate type along the way to becoming a mature liver or pancreas cell.

Investigators want to make embryonic stem cells for liver or pancreatic beta cells for therapies and research. To do this, they mimic the embryonic developmental steps to proceed from an embryonic stem cell to a mature cell, but have no way of knowing if they are on the right track. The hope is that the findings from this study can be applied to assess the epigenetic state of intermediate progenitor cells.

"By better understanding how a cell is normally programmed we will eventually be able to properly reprogram other cells," notes Zaret. In the near term, the team also aims to generate liver and pancreas cells for research and to screen drugs that repair defects or facilitate cell growth.

With regenerated cells, researchers hope to one day fill the acute shortage in pancreatic and liver tissue available for transplantation in cases of type I diabetes and acute liver failure.

Source: University of Pennsylvania School of Medicine
Contact: Karen Kreeger

Reference:
Chromatin “Prepattern” and Histone Modifiers in a Fate Choice for Liver and Pancreas
Cheng-Ran Xu, Philip A. Cole, David J. Meyers, Jay Kormish, Sharon Dent, and Kenneth S. Zaret
Science 20 May 2011, Vol. 332 no. 6032 pp. 963-966, DOI: 10.1126/science.1202845
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Sections of Retinas Regenerated with Stem Cells from Skin

Visual function increased to almost half of normal retina
Tuesday, 17 May 2011

Scientists from Schepens Eye Research Institute are the first to regenerate large areas of damaged retinas and improve visual function using iPS cells (induced pluripotent stem cells) derived from skin. The results of their study, which is published in PLoS ONE this month, hold great promise for future treatments and cures for diseases such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and other retinal diseases that affect millions worldwide.

"We are very excited about these results," says Dr. Budd A. Tucker, the study's first author.

"While other researchers have been successful in converting skin cells into induced pluripotent stem cells (iPSCs) and subsequently into retinal neurons, we believe that this is the first time that this degree of retinal reconstruction and restoration of visual function has been detected," he adds. Tucker, who is currently an Assistant Professor of Ophthalmology at the University of Iowa, Carver College of Medicine, completed the study at Schepens Eye Research Institute in collaboration with Dr. Michael J. Young, the principle investigator of the study, who heads the Institute's regenerative medicine centre.

Today, diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are the leading causes of incurable blindness in the western world. In these diseases, retinal cells, also known as photoreceptors, begin to die and with them the eye's ability to capture light and transmit this information to the brain. Once destroyed, retinal cells, like other cells of the central nervous system have limited capacity for endogenous regeneration.

"Stem cell regeneration of this precious tissue is our best hope for treating and someday curing these disorders," says Young, who has been at the forefront of vision stem cell research for more than a decade.

While Tucker, Young and other scientists were beginning to tap the potential of embryonic and adult stem cells early in the decade, the discovery that skin cells could be transformed into "pluripotent" cells, nearly identical to embryonic cells, stirred excitement in the vision research community. Since 2006 when researchers in Japan first used a set of four "transcription factors" to signal skin cells to become iPSCs, vision scientists have been exploring ways to use this new technology. Like embryonic stem cells, iPSCs have the ability to become any other cell in the body, but are not fraught with the ethical, emotional and political issues associated with the use of tissue from human embryos.

Tucker and Young harvested skin cells from the tails of red fluorescent mice. They used red mice, because the red tissue would be easy to track when transplanted in the eyes of non-fluorescent diseased mice.

By forcing these cells to express the four Yamanaka transcription factors (named for their discoverer) the group generated red fluorescent iPSCs, and, with additional chemical coaxing, precursors of retinal cells. Precursor cells are immature photoreceptors that only mature in their natural habitat — the eye.

Within 33 days, the cells were ready to be transplanted and were introduced into the eyes of a mouse model of retina degenerative disease. Due to a genetic mutation, the retinas of these recipient mice quickly degenerate, the photoreceptor cells die and at the time of transplant electrical activity, as detected by ERG (electroretinography), are absent.

Within four to six weeks, the researchers observed that the transplanted "red" cells had taken up residence in the appropriate retinal area (photoreceptor layer) of the eye and had begun to integrate and assemble into healthily looking retinal tissue.

The team then retested the mice with ERG and found a significant increase in electrical activity in the newly reconstructed retinal tissue. In fact, the amount of electrical activity was approximately half of what would be expected in a normal retina. They also conducted a dark adaption test to see if connections were being made between the new photoreceptor cells and the rest of the retina. In brief, the group found that by stimulating the newly integrated photoreceptor cells with light they could detect a signal in the downstream neurons, which was absent in the other untreated eye.

Based on the results of their study, Tucker and Young believe that harvesting skin cells for use in retinal regeneration is and will continue to be a promising resource for the future.

The two scientists say their next step will be to take this technology into large animal models of retinal degenerative disease and eventually toward human clinical trials.

Source: Schepens Eye Research Institute
Contact: Patti Jacobs

Reference:
Transplantation of Adult Mouse iPS Cell-Derived Photoreceptor Precursors Restores Retinal Structure and Function in Degenerative Mice
Budd A. Tucker, In-Hyun Park, Sara D. Qi, Henry J. Klassen, Caihui Jiang, Jing Yao, Stephen Redenti, George Q. Daley, Michael J. Young
PLoS ONE 6(4): e18992. doi:10.1371/journal.pone.0018992
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iPS Cells Trigger Immune Reactions in Mice

Study finds therapies using induced pluripotent stem cells could encounter immune rejection problems
Saturday, 14 May 2011

An infiltration of T cells, shown by dark brown
colour, can be seen in the tissues formed by
iPSCs. Credit: Yang Xu, UC San Diego.

Biologists at UC San Diego have discovered that an important class of stem cells known as "induced pluripotent stem cells," or iPSCs, derived from an individual's own cells, could face immune rejection problems if they are used in future stem cell therapies.

In today's advance online issue of the journal Nature, the researchers report the first clear evidence of immune system rejection of cells derived from autologous iPSCs that can be differentiated into a wide variety of cell types.

Because iPSCs are not derived from embryonic tissue and are not subject to the federal restrictions that limit the use of embryonic stem cells, researchers regard them as a promising means to develop stem cell therapies. In addition, because iPSCs are derived from an individual's own cells, many scientists had assumed that these stem cells would not be recognized by the immune system. Therefore, the immune system would not try to mount an attack to purge them from the body.

In fact, scientists regarded iPSCs as particularly attractive candidates for clinical use because cells derived from embryonic stem cells will induce immune system rejection that requires physicians to administer immune suppressant medications that can compromise a person's overall health.

However, the UCSD biologists, funded by NIH and an early translational grant from the California Institute for Regenerative Medicine, the state's stem-cell funding agency, found that iPSCs are subject to some of the same problems of immune system rejection as embryonic stem cells.

"The assumption that cells derived from iPSCs are totally immune tolerant has to be re-evaluated before considering human trials," says Yang Xu, a professor of biology at UCSD who headed the team that published the study.

His team of biologists — which included postdoctoral researchers Tongbiao Zhao, Zhen-Ning Zhang and Zhili Rong — reached that conclusion after testing the immune response of an inbred strain of mice to embryonic stem cells and several types of iPSCs derived from the same strain of inbred mice.

The scientists found, not surprisingly, that the immune system of one mouse could not recognize the cells derived from embryonic stem cells of the same strain of mice. But the experiments also showed that the immune system rejected cells derived from iPSCs reprogrammed from fibroblasts of the same strain of mice, mimicking the situation whereby a patient would be treated with cells derived from iPSCs reprogrammed from the patient's own cells. The scientists also found that the abnormal gene expression during the differentiation of iPSCs causes the immune responses.

"This result doesn't suggest that iPSCs cannot be used clinically," says Xu.

"It is important now to look at exactly what types of cells derived from iPSCs — and there probably are not that many based on our findings — are likely to generate immune system rejection."

"Our immune response assay is a robust method for checking the immune tolerance, and therefore, the safety of iPSC that may be developed," he added.

“As with any new technology, there is always this initial phase of infatuation, and then the reality sets in,” told Dr. George Q. Daley, director of the stem cell transplantation program at Children’s Hospital Boston, to New York Times.

“I think it goes to the heart of the issue of how ignorant we really are in understanding these cells”.

“The path to the clinic has just gotten a lot murkier,” said Dr. Robert Lanza to New York Times, chief scientific officer of Advanced Cell Technology, a company trying to develop medical treatments using both embryonic stem cells and induced pluripotent stem cells.

“This reopens the whole need for S.C.N.T, which will be controversial,” said Dr. Lanza, referring to somatic cell nuclear transfer, the scientific term for cloning.

“We had thought we had put that aside with this technology.”

Source: University of California at San Diego and N.Y. Times.
Contact: Kim McDonald
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Human Lung Stem Cell Discovered

The lung stem cell has a crucial role in tissue regeneration and may promote restoration of damaged lung cells
Thursday, 12 May 2011

For the first time, researchers at Brigham and Women's Hospital (BWH) have identified a human lung stem cell that is self-renewing and capable of forming and integrating multiple biological structures of the lung including bronchioles, alveoli and pulmonary vessels. This research is published in the May 12, 2011 issue of the New England Journal of Medicine.

"This research describes, for the first time, a true human lung stem cell. The discovery of this stem cell has the potential to offer those who suffer from chronic lung diseases a totally novel treatment option by regenerating or repairing damaged areas of the lung," said Piero Anversa, MD, director of the Center for Regenerative Medicine at Brigham and Women's Hospital and corresponding author.

Using lung tissue from surgical samples, researchers identified and isolated the human lung stem cell and tested the functionality of the stem cell both in vitro and in vivo. Once the stem cell was isolated, researchers demonstrated in vitro that the cell was capable of dividing both into new stem cells and also into cells that would grow into various types of lung tissue. Next, researchers injected the stem cell into mice with damaged lungs. The injected stem cells differentiated into new bronchioles, alveoli and pulmonary vessel cells, which not only formed new lung tissue, but also integrated structurally to the existing lung tissue in the mice.

The researchers define this cell as truly "stem" because it fulfils the three categories necessary to fall under stem cell categorization: first, the cell renews itself; second, it forms into many different types of lung cells; and third, it is transmissible, meaning that after a mouse was injected with the stem cells and responded by generating new tissue, researchers were then able to isolate the stem cell in the treated mouse, and use that cell in a new mouse with the same results.

"These are the critical first steps in developing clinical treatments for those with lung disease for which no therapies exist. Further research is needed, but we are excited about the impact this discovery could have on our ability to regenerate or recreate new lung tissues to replace damaged areas of the lungs," said Joseph Loscalzo, MD, PhD, chair of the Department of Medicine at BWH and co-author.

Source: Brigham and Women's Hospital
Contact: Lori J. Shanks
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Adult Stem Cells Take Root in Livers and Repair Damage

Adult Stem Cells Take Root in Livers and Repair Damage
Thursday, 12 May 2011

Johns Hopkins researchers have demonstrated that human liver cells derived from adult cells coaxed into an embryonic state can engraft and begin regenerating liver tissue in mice with chronic liver damage.

These are regenerative liver cells eight

weeks after transplantation. Credit:

Yoon-Young Jang.

The work, published in the May 11 issue of the journal Science Translational Medicine, suggests that liver cells derived from so-called "induced-pluripotent stem cells (iPSCs)" could one day be used as an alternative to liver transplant in patients with serious liver diseases, bypassing long waiting lists for organs and concerns about immune system rejection of donated tissue.

"Our findings provide a foundation for producing functional liver cells for patients who suffer liver diseases and are in need of transplantation," says Yoon-Young Jang, M.D., Ph.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center.

"iPSC-derived liver cells not only can be generated in large amounts, but also can be tailored to each patient, preventing immune-rejection problems associated with liver transplants from unmatched donors or embryonic stem cells."

iPSCs are made from adult cells that have been genetically reprogrammed to revert to an embryonic stem cell-like state, with the ability to transform into different cell types. Human iPSCs can be generated from various tissues, including skin, blood and liver cells.

Although the liver can regenerate in the body, end-stage liver failure caused by diseases like cirrhosis and cancers eventually destroy the liver's regenerative ability, Jang says. Currently, the only option for those patients is to receive a liver organ or liver cell transplant, a supply problem given the severe shortage of donor liver tissue for transplantation. In addition, mature liver cells and adult liver stem cells are difficult to isolate or grow in the laboratory, she says. By contrast, iPSCs can be made from a tiny amount of many kinds of tissue; and the embryonic stem-like iPSCs can grow in laboratory cultures indefinitely.

For the study, Jang and colleagues generated human iPSCs from a variety of adult human cells, including liver cells, fibroblasts (connective tissue cells), bone marrow stem cells and skin cells. They found that though the iPSCs overall were molecularly similar to each other and to embryonic stem cells, they retained a distinct molecular "signature" inherited from the cell of origin.

Next, they chemically induced the iPSCs to differentiate first into immature and then more mature liver cell types. Regardless of their origin, the different iPSC lines all showed the same ability to develop into liver cells.

Using mice with humanlike liver cirrhosis, the researchers then injected the animals either with 2 million human iPSC-derived liver cells or with normal human liver cells. They discovered that the iPSC-derived liver cells engrafted to the mouse liver with an efficiency of eight to 15 percent, a rate similar to the engraftment rate for adult human liver cells at 11 percent.

Researchers also found the engrafted iPSCs worked well. The scientists detected proteins normally secreted by adult human liver cells, including albumin, alpha-1-antitrypsin, transferrin and fibrinogen, in the blood of mice transplanted with human iPSC-derived liver cells.

Additional studies will need to be completed before clinical trials can begin, Jang says. One concern has been the potential for embryonic stem cells or iPSCs to cause tumours, though no tumours formed in any of the transplanted mice during the seven months they were studied (equating to more than 30 years in a human life). The scientists also plan to evaluate the impact of molecular memory that may linger in iPSCs for other type of cellular fate changes.

Source: Johns Hopkins Medical Institutions
Contact: Vanessa Wasta
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Stem Cells Help Create Blood Vessel in Life-Saving Surgery

Stem cell technology used in unique surgery of 10-year-old girl Monday, 09 May 2011

A 10-year-old girl with a deadly blood clot underwent a life-saving surgery that showed the power of using stem cells to regenerate healthy organs.

Surgeon and professor Michael

Olausson. Credit: Björn Larsson

Rosvall.

The girl developed a clot in the blood vessel between her intestine and liver during her first year of life, creating the risk of potentially fatal bleeding. Michael Olausson, a surgeon at Sahlgrenska University Hospital at the University of Gothenburg took a blood vessel from a donor, chemically removed tissue and DNA from it, then seeded stem cells from the girl’s bone marrow to create a healthy, living blood vessel.

Surgeon and Professor Michael Olausson were able to create a new connection with the aid of this blood vessel between the liver and the intestines, necessary to cure the girl. The girl is now in good health, and her prognosis is very good. The girl developed during her first year of life a blood clot in the blood vessel that leads blood from the intestines to the liver. This introduced the risk that she would experience life-threatening internal bleeding. The condition can be cured if it is possible to direct the blood along the correct path, back into the liver. In optimal cases, the surgery can be performed using blood vessels from other parts of the patient's body, but a liver transplant may be necessary if the surgery is unsuccessful due to a lack of sufficient blood vessels. A liver transplant will involve subsequent lifelong treatment with immunosuppressive drugs.

Blood vessels from a dead donor were used in the present case. The vessel was then chemically treated to remove all cells RNA and DNA. This left just the supporting tissue. Stem cells were then obtained from the girl's bone marrow and these were added to the supporting tissue. A new blood vessel grew in just under four weeks. This was used during the surgery in order to create the new connection between the liver and the intestines, necessary to cure the girl.

"We carried out the surgery over three months ago now, and the result was very good, with no serious complications. To our knowledge this is the first procedure of this type in the world,” says Michael Olausson.

“The girl is in good health, and we believe that her prognosis is very good. Since the vessel was created with the girl's own stem cells, she does not need to take drugs to prevent rejection", says Michael Olausson at the Transplant Centre, Sahlgrenska University Hospital and professor at the Sahlgrenska Academy.

The procedure shows that it is possible to create new blood vessels from stem cells, using a previous blood vessel as a template. This can lead to the condition that the girl suffered from being treated more easily, and with less risk for the patient. The result of this operation may have implications not only for the condition the girl was suffering from, but also in a number of other fields of research.

"The next step is to intensify research into the recreation of other organs, and to develop methods that can be used for arteries. This can help, among others, patients who need dialysis and those needing surgery for the coronary arteries. It may also help those needing complete organs", says Michael Olausson.

"There may also be major financial benefits for the healthcare system, particularly if it proves possible to produce, for example, complete kidneys by this method, since the consumption of drugs will be dramatically reduced. For the patients, it means that the undesired effects of the drugs that must currently be used will be avoided."

Source: University of Gothenburg
Contact: Michael Olausson
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Normal Stem Cells Made to Look and Act Like Cancer Stem Cells

Normal Stem Cells Made to Look and Act Like Cancer Stem Cells
Thursday, 05 May 2011

Researchers at the University of North Carolina School of Medicine at Chapel Hill, after isolating normal stem cells that form the developing placenta, have given them the same properties of stem cells associated with an aggressive type of breast cancer.

From left to right are study co-first

authors Nicole Vincent Jordan and

Amy N. Abell, Ph.D. Credit: Photo

by Les Lang/UNC School of

Medicine.

The scientific first opens the door for developing novel targeted therapies aimed at triple negative breast cancer. Known also as TNBC, this highly recurrent tumour spreads aggressively beyond its original site in the breast and carries a poor prognosis for patients who have it.

The study will be published online Friday, May 6, by the journal Cell Stem Cell.

"We changed only one amino acid in normal tissue stem cells, trophoblast stem cells. While they maintained their self-renewal, these mutant stem cells had properties very similar to what people predict in cancer stem cells: they were highly mobile and highly invasive," said Gary Johnson, PhD, professor and chair of pharmacology at UNC and senior study author.

"No one has ever isolated a stem cell like that." Johnson is also a member of the UNC Lineberger Comprehensive Cancer Center.

In normal development, epithelial stem cells called trophoblasts are involved in the formation of placental tissue. To do so, they must undergo a conversion to tissue-like cells. These then travel to the site in the uterus where they revert to a non-invasive tissue cell.

"But the mutant trophoblast stem cells made in our lab, which would normally invade the uterus and then stop, just keep going," Johnson said.

The study led by the first authors, research assistant professor Amy N. Abell, PhD and graduate student Nicole Vincent Jordan, both working in Johnson's lab, showed that similar to triple-negative breast cancer stem cells, normal tissue stem cells also go through the same program of molecular changes during organ development called epithelial mesenchymal transition, or EMT. This suggests that breast cancer cells utilize this tissue stem cell molecular program for tumour metastasis, or cancer spread.

The discovery was made using a unique mouse model of tissue stem cell EMT developed in the Johnson laboratory. The study identified two proteins that regulate the expression of specific genes in tissue stem cells during organ development that control normal EMT. Inactivation of the proteins MAP3K4 and CBP in trophoblast stem cells causes them to become hyper invasive.

In collaboration with Aleix Prat, PhD and Charles Perou, PhD in the UNC Lineberger Comprehensive Cancer Center, the research team made another discovery: an overlap between the gene expression signature of the mutant tissue stem cells properties during EMT and the triple-negative human breast cancer gene signature that's predictive of invasiveness. The same genes were down regulated.

"This significant genetic intersection between tissue stem cells and TNBC has identified previously unrecognized genes that likely contribute to breast cancer metastasis," said Johnson.

"This newly identified gene signature is currently being investigated in different models of breast cancer with the goal of developing new therapeutic interventions for the treatment of TNBC."

Source: University of North Carolina School of Medicine
Contact: Les Lang
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Researchers in Brazil Establish the First Line of Human Embryonic Stem Cells

Researchers in Brazil Establish the First Line of Human Embryonic Stem Cells
Tuesday, 03 May 2011

Brazilian researchers, reporting in the current issue of Cell Transplantation, discovered difficulties in establishing a genetically diverse line of human embryonic stem cells (hESC) to serve the therapeutic stem cell transplantation needs of the diverse ethnic and genetic Brazilian population.

According to the study's corresponding author, Dr. Lygia V. Pereira of the Molecular Genetics Laboratory at the University of Sao Paulo, Brazil, pluripotent human embryonic stem cells are an important tool for basic and applied stem cell transplantation research. However, immunocompatibility is an issue, especially in a genetically diverse population such as that in Brazil where the population is comprised of European, African and Native South American ancestry.

In their study, the researchers developed an hES cell line (the first in South America) they called "BR-1" derived from a Brazilian population with embryos donated by couples who had sought assistance from private fertility clinics. Their research was compatible with the 2005 Brazilian national legal, ethical and clinical guidelines for embryonic stem cell research using tissue that had been frozen for the legally mandated time of at least three years, and that had been produced for reproductive reasons.

Their results showed that the hES cell lines they established were a "worse match" to the Brazilian population than hESC lines developed elsewhere, particularly those developed in the U.S. and Singapore.

The reasons for that may be several, said Dr. Pereira.

"The Brazilian population is one of the most heterogeneous in the world, and the genes of Brazilians are mosaics," said Dr. Pereira.

"However, an analysis of BR-1 showed that it is mostly European in origin. The reproductive assistance offered by the Brazilian public health system does not include cryopreservation of surplus embryos, meaning that the only research material available came from private clinics where couples with above-average incomes could afford the high cost of assisted reproduction."

According to the researchers, that segment of the Brazilian population is mostly composed of people self-identified as white - of European ancestry - and so is not representative of Brazilian ethnic admixture and, thus, is unable to be widely compatible with Brazil's diverse population genetics.

"Although we have successfully established the first line of hESCs from the Brazilian population that adds to the pool of genetically different pluripotent cells available, it will be important to have access to embryos from the more mixed population and assistance from the Public Health System," concluded Dr. Pereira.

"Use of embryonic stem cells (ES) in regenerative medicine is very promising, but the potential problems of tumour development, cell rejection due to histo-incompatibility, and contamination with animal products employed in the cell culture need to be overcome," said Dr. Julio Voltarelli, professor of Clinical Medicine and Clinical Immunology at the University of Sao Pãulo, Brazil and section editor for Cell Transplantation.

"In this study, Dr Pereira and colleagues compared the HLA compatibility between their ESC line, the first established in Brazil, and a sample of the Brazilian population who volunteered as donors for hematopoietic stem cell transplantation (REDOME). They found few matches for the ESC line in the representative population, which was attributed to the great genetic heterogeneity of the Brazilian population. This finding may add another difficulty to the clinical use of ESC in Brazil and other mixed populations even once the safety issues of ESC lines are resolved."

Source: Florida Science Communications
Contact: Randolph Fillmore

Reference:
Establishment Of A Brazilian Line Of Human Embryonic Stem Cells In Defined Medium – Implications For Cell Therapy In An Ethnically Diverse Population
Fraga, A. M.; Sukoyan, M.; Rajan, P.; Braga, D. P. F.; Iaconelli, A., Jr.; Franco, J. G., Jr.; Borges, E., Jr.; Pereira, L. V.
Cell Transplant. 20(3):431-440; 2011.
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ZenMaster

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