Wednesday 26 January 2011

Chinese Academy of Sciences Initiates "Trailblazing" Stem Cell Research Project

Chinese Academy of Sciences Initiates "Trailblazing" Stem Cell Research Project
Wednesday, 26 January 2011

The Chinese Academy of Sciences (CAS) on Tuesday announced it has initiated a "strategic, trailblazing" research project on stem cells and regenerative medicine.

The project mainly aims to remove the bottlenecks China is confronted with in stem cell research, the CAS said in its 2011 work meeting in Beijing.

The project will focus on the research of stem cell regulations, core mechanisms for stem cell therapies, and other key technologies, it said.

The CAS said it would establish a world-class research platform and base for stem cell and regenerative medicine research through the project.

The stem cell research project is one of eight such trailblazing projects of the CAS. The others include projects on nuclear fission, space science and clean energy.

Source: Chinese Academy of Sciences
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Thursday 20 January 2011

Mother's Stem Cells Key to Treating Genetic Disease before Birth

Mother's Stem Cells Key to Treating Genetic Disease before Birth
Thursday, 20 January 2011

UCSF researchers have tackled a decade-long scientific conundrum, and their discovery is expected to lead to significant advances in using stem cells to treat genetic diseases before birth. Through a series of mouse model experiments, the research team determined that a mother's immune response prevents a foetus from accepting transplanted blood stem cells, and yet this response can be overcome simply by transplanting cells harvested from the mother herself.

"This research is really exciting because it offers us a straightforward, elegant solution that makes foetal stem cell transplantation a reachable goal," said senior author Tippi MacKenzie, MD, an assistant professor of paediatric surgery at UCSF and foetal surgeon at UCSF Benioff Children's Hospital.

"We now, for the first time, have a viable strategy for treating congenital stem cell disorders before birth."

Scientists have long viewed in utero blood stem cell transplantation as a promising treatment strategy for many genetic diseases diagnosed as early as the first trimester of pregnancy, including sickle cell disease and certain immune disorders. Foetal stem cell transplantation involves taking healthy cells from the bone marrow of a donor and transplanting them into the foetus through ultrasound-guided injections. When successful, the implanted cells, or graft, replenish the patient's supply of healthy blood-forming cells.

In theory, the developing foetus with an immature immune system should be a prime target for successful transplantation, since the risk of graft rejection is low and the need for long-term immunosuppressive therapy may be avoided. However, most previous attempts to transplant blood stem cells into a human foetus have been unsuccessful, prompting some researchers to lose interest in this promising field, according to MacKenzie, who also is an investigator with the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.

Findings from the study will appear online January 18, 2011, in the Journal of Clinical Investigation. They also will be published in the journal's February 2011 issue.

"The fact that foetal stem cell transplantation has not been very successful has been puzzling, especially given the widely accepted dogma that the immature foetal immune system can adapt to tolerate foreign substances," said co-senior author Qizhi Tang, PhD, an assistant professor of transplant surgery and director of the UCSF Transplantation Research Lab..

"The surprising finding in our study is that the mother's immune system is to blame."

In the study's first phase, researchers examined the cellular content of foetal mouse blood and found a large proportion of maternal blood cells in the foetus. Their analyses indicated that up to 10 percent of the foetus' blood cells came from the mother – a significantly larger percentage of maternal cells than what is found anywhere else in the foetus.

"We had previously known that a minute amount of cells travel from the mother into a developing foetus and that this is an important tolerance mechanism in all healthy pregnancies," MacKenzie said.

"However, the unexpectedly large proportion of maternal blood cells in the foetus made us think that perhaps it was the maternal, rather than the foetal, immune response that poses the real barrier to effective stem cell transplantation."

To further investigate this hypothesis, the team transplanted foetal mice with blood stem cells from a second strain of mice that were not matched to the foetus or the mother. Following transplantation, the researchers observed an influx of T cells – the major driving force behind an immune response – from the mother into the foetus, which subsequently led to rejection of the transplanted graft.

However, if the researchers removed T cells only from the mother before carrying out the transplant, nearly 100 percent of the injected foetuses engrafted, or accepted the transplanted cells, indicating that maternal T cells play the critical role in triggering transplant rejection. Finally, the researchers transplanted foetal mice with blood stem cells matched to the mother, which, as expected, resulted in a very high success rate.

"As long as the transplanted stem cells are matched to the mother, it does not seem to matter if they are matched to the foetus," said first author Amar Nijagal, MD, a postdoctoral research fellow and surgery resident at UCSF.

"Transplanting stem cells harvested from the mother makes sense because the mother and her developing foetus are prewired to tolerate each other."

As next steps, researchers will need to confirm that the findings are consistent in humans and will investigate how exactly maternal T cells cause a graft rejection.

"Now that we know a foetus can become tolerant to a foreign stem cell source, we can really think big and consider looking at how other types of stem cells might be used to treat everything from neurological disorders to muscular disorders before birth," MacKenzie added.

Source: University of California at San Francisco
Contact: Kate Vidinsky

Reference:
Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice
Amar Nijagal, Marta Wegorzewska, Erin Jarvis, Tom Le, Qizhi Tang, Tippi C. MacKenzie
J Clin Invest. 2011, doi:10.1172/JCI44907
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Skin Provides Australia's First iPS cells for Rare Genetic Disease

Skin Provides Australia's First iPS cells for Rare Genetic Disease
Thursday, 20 January 2011

Scientists have developed Australia's first adult induced pluripotent stem cell lines using skin biopsies from patients with the rare genetic disease Friedreich Ataxia (FA).

The study was conducted by the University of Melbourne and Monash Institute of Medical Research and is published in the current online edition of the international journal Stem Cell Reviews and Reports. It is the first time adult pluripotent stem cells, known as iPS cells have been developed for a specific disease in Australia, allowing for the development of new treatments for FA and related conditions such as diabetes and heart disease.

Induced pluripotent stem (iPS) cells result from the reprogramming of adult cells, such as skin cells, and are similar to embryonic stem cells in that they have the potential to generate any cell type of the body.

Dr Alice Pébay and Dr Mirella Dottori, co-leaders of the study from University of Melbourne, characterized and directed the Friedreich Ataxia iPS cells to become specific cell types, including heart cells and nerves, which are normally not functioning well in the disease.

"By focusing on the heart and nerve cell types, we hope to be able to develop treatments to improve heart function and the loss of movement experienced by patients with FA," Dr Pébay said.

Friedreich Ataxia affects one in 30,000 people globally, and Dr Paul Verma of the Monash Institute of Medical Research said this research could be applied to other diseases.

"Due to the number of symptoms experienced by people with FA, including diabetes and heart disease, this resource could be applied to developing treatment for those conditions and helping even more people," he said.

Dr Dottori said the research could not have been achieved without a significant network of experts and support from the Friedreich Ataxia Research Association (Australasia) (FARA-A) and the Friedreich Ataxia Research Alliance (FARA) in the United States.

"It is the collective effort of clinicians, scientists, patients and FARA that has made this discovery possible," she said.

Ms Varlli Beetham, Executive Director of FARA said the finding provided real hope for people suffering the debilitating condition.

"We are proud to have supported this research effort and look forward to the next stage of research, the development of new trial treatments," she said.

Source: University of Melbourne
Contact: Emma O'Neill

Reference:
Generation of Induced Pluripotent Stem Cell Lines from Friedreich Ataxia Patients
Jun Liu, Paul J. Verma, Marguerite V. Evans-Galea, Martin B. Delatycki, Anna Michalska, Jessie Leung, Duncan Crombie, Joseph P. Sarsero, Robert Williamson, Mirella Dottori and Alice Pébay
Stem Cell Reviews and Reports, DOI: 10.1007/s12015-010-9210-x
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Embryonic Stem Cells Help Deliver 'Good Genes' in a Model of Inherited Blood Disorder

Embryonic Stem Cells Help Deliver 'Good Genes' in a Model of Inherited Blood Disorder
Thursday, 20 January 2011

Researchers at Nationwide Children's Hospital report a gene therapy strategy that improves the condition of a mouse model of an inherited blood disorder, Beta Thalassaemia. The gene correction involves using unfertilized eggs from afflicted mice to produce a batch of embryonic stem cell lines. Some of these stem cell lines do not inherit the disease gene and can thus be used for transplantation-based treatments of the same mice. Findings could hold promise for a new treatment strategy for autosomal dominant diseases like certain forms of Beta Thalassaemia, tuberous sclerosis or Huntington's disease.

Embryonic stem cells have the potential to produce unlimited quantities of any cell type and are therefore being explored as a new therapeutic option for many diseases. Unfertilized eggs can be cultured to form embryonic stem cells, so-called parthenogenetic embryonic stem cells.

"Parthenogenetic embryonic stem cells can differentiate into multiple tissue types as do stem cells from fertilized embryos," said K. John McLaughlin, PhD, principal investigator in the Center for Molecular and Human Genetics at The Research Institute at Nationwide Children's Hospital, Columbus, OH. Previously, the group demonstrated that blood cells derived from parthenogenetic cells could provide healthy, long-term blood replacement in mice.

"Advantages of parthenogenetic stem cells are not only that fertilization is not needed, but also that the recipient's immune system may potentially not view them as foreign, minimizing rejection problems. Furthermore, since parthenogenetic embryonic stem cells are derived from reproductive cells which contain only a single set of the genetic information instead of the double set present in body cells, they may not contain certain abnormal genes present in the other copy," said Dr. McLaughlin also one of the study authors.

A single copy of an abnormal gene inherited from one parent can cause so-called autosomal dominant diseases such as tuberous sclerosis or Huntington's disease. The affected person has one defective and one normal copy of the gene, but the abnormal gene overrides the normal gene, causing disease. In normal sexual reproduction, each parent provides one gene copy to offspring via their reproductive cells. Therefore, the reproductive cells of a patient with an autosomal dominant disease could either pass along a defective copy or a normal copy.

"As the donor patient has one defective gene copy and one normal, and only one copy is used for normal reproduction, we can select egg-cell-derived embryonic stem cells with two normal copies," said Dr. McLaughlin.

"These single-parent/patient-derived embryonic stem cells can theoretically be used for correction of a diverse number of diseases that occur when one copy of the gene is abnormal," said Dr. McLaughlin.

To test this theory, Dr. McLaughlin and colleagues from the University of Pennsylvania, University of North Carolina and University of Minnesota, examined whether parthenogenetic embryonic stem cells could be used for tissue repair in a mouse model of thalassaemia intermedia. Thalassaemia intermedia is an inherited blood disorder in which the body lacks sufficient normal haemoglobin, leading to excessive destruction of red blood cells and anaemia. They used a mouse model in which one defective gene copy causes anaemia.

Using approaches developed from a previous study done by this group, Nationwide Children's Research Fellow Sigrid Eckardt, PhD, derived embryonic stem cells from the unfertilized eggs of female mice with the disease, and identified those stem cell lines that contained only the "healthy" haemoglobin genes. These "genetically clean" embryonic stem cell lines were converted into cells that were transplanted into afflicted mice that were carriers of the disease-causing gene. Blood samples drawn five weeks after transplantation revealed that the delivered cells were present in the recipients' blood. Their red blood cells were also corrected to a size similar to normal mice and red blood cell count, hematocrit and haemoglobin levels became normal.

"Overall, we observed long-term improvement of thalassaemia in this model," said Dr. Eckardt.

"Our findings suggest that using reproductive cells to generate embryonic stem cells that are 'disease-free' may be a solution for genetic diseases involving large, complex or poorly identified deletions in the genome or that are not treatable by current gene therapy approaches."

Dr. McLaughlin says that this approach also contrasts with typical gene therapy approaches in that it requires no engineering of the genome, which is currently difficult to achieve in human embryonic and embryonic-like (IPS) stem cells.

Source: Nationwide Children's Hospital
Contact: Erin Pope
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ZenMaster


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Genetic Abnormalities Identified in Pluripotent Stem Cell Lines

Genetic Abnormalities Identified in Pluripotent Stem Cell Lines
Thursday, 20 January 2011

A multinational team of researchers led by stem cell scientists at the University of California, San Diego School of Medicine and Scripps Research Institute has documented specific genetic abnormalities that occur in human embryonic (hESC) and induced pluripotent stem cell (iPSC) lines. Their study, "Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture" will be published in the January 7 issue of the journal Cell Stem Cell.

The published findings highlight the need for frequent genomic monitoring of pluripotent stem cells to assure their stability and clinical safety.

"We found that human pluripotent cells (hESCs and iPSCs) had higher frequencies of genomic aberrations than other cell types," said Louise Laurent, MD, PhD, assistant professor in the UCSD Department of Reproductive Medicine and first author on the study.

"Most strikingly, we observed a higher frequency of genomic duplications in hESCs and deletions in iPSCs, when compared to non-pluripotent samples."

The ability of human pluripotent stem cells to become every cell type in the body has made them potential sources of differentiated cells for cell replacement therapies.

"Since genetic aberrations are often associated with cancers, it is vital that cell lines destined for clinical use are free from cancer-associated genomic alterations," said senior author Jeanne F. Loring, PhD, professor and Director of the Center for Regenerative Medicine at the Scripps Research Institute.

The team identified regions in the genome that had a greater tendency to become abnormal in pluripotent cell lines. With hESCs, the observed abnormalities were most often duplications near pluripotency-associated genes; in iPSC lines, there were duplications involving cell proliferation genes and deletions associated with tumour suppressor genes.

These changes could not have been detected by traditional microscopic techniques such as karyotyping. The team instead used a high-resolution molecular technique called "single nucleotide polymorphism" (SNP) analysis, which allowed them to look for genetic changes at more than a million sites in the human genome.

"We were surprised to see profound genetic changes occurring in some cultures over very short periods of time, such as during the process of reprogramming somatic cells into iPSCs and during differentiation of the cells in culture," Laurent said.

"We don't know yet what effects, if any, these genetic abnormalities will have on the outcome of basic research studies or clinical applications, and we need to find out."

Loring concluded:

"The results of the study illustrate the need for frequent genomic monitoring of pluripotent stem cell cultures. SNP analysis has not been a part of routine monitoring of hESC and iPSC cultures, but our results suggest that perhaps it should be."

Source: University of California at San Diego
Contact: Debra Kain

Reference:
Dynamic Changes in the Copy Number of Pluripotency and Cell Proliferation Genes in Human ESCs and iPSCs during Reprogramming and Time in Culture
Louise C. Laurent, Igor Ulitsky, Ileana Slavin, Ha Tran, Andrew Schork, Robert Morey, Candace Lynch, Julie V. Harness, Sunray Lee, Maria J. Barrero, Sherman Ku, Marina Martynova, Ruslan Semechkin, Vasiliy Galat, Joel Gottesfeld, Juan Carlos Izpisua Belmonte, Chuck Murry, Hans S. Keirstead, Hyun-Sook Park, Uli Schmidt, Andrew L. Laslett, Franz-Josef Muller, Caroline M. Nievergelt, Ron Shamir, Jeanne F. Loring
Cell Stem Cell, Volume 8, Issue 1, 106-118, 7 January 2011, 10.1016/j.stem.2010.12.003
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