Monthly Archives: October 2013

PUBLIC RELEASE DATE:

25-Oct-2013

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

LOS ANGELES (Oct. 25, 2013) Although the technology has existed for just a few years, scientists increasingly use "disease in a dish" models to study genetic, molecular and cellular defects. But a team of doctors and scientists led by researchers at the Cedars-Sinai Regenerative Medicine Institute went further in a study of Lou Gehrig's disease, a fatal disorder that attacks muscle-controlling nerve cells in the brain and spinal cord.

After using an innovative stem cell technique to create neurons in a lab dish from skin scrapings of patients who have the disorder, the researchers inserted molecules made of small stretches of genetic material, blocking the damaging effects of a defective gene and, in the process, providing "proof of concept" for a new therapeutic strategy an important step in moving research findings into clinical trials.

The study, published Oct. 23 in Science Translational Medicine, is believed to be one of the first in which a specific form of Lou Gehrig's disease, or amyotrophic lateral sclerosis, was replicated in a dish, analyzed and "treated," suggesting a potential future therapy all in a single study.

"In a sense, this represents the full spectrum of what we are trying to accomplish with patient-based stem cell modeling. It gives researchers the opportunity to conduct extensive studies of a disease's genetic and molecular makeup and develop potential treatments in the laboratory before translating them into patient trials," said Robert H. Baloh, MD, PhD, director of Cedars-Sinai's Neuromuscular Division in the Department of Neurology and director of the multidisciplinary ALS Program. He is the lead researcher and the article's senior author.

Laboratory models of diseases have been made possible by a recently invented process using induced pluripotent stem cells cells derived from a patient's own skin samples and "sent back in time" through genetic manipulation to an embryonic state. From there, they can be made into any cell of the human body.

The cells used in the study were produced by the Induced Pluripotent Stem Cell Core Facility of Cedars-Sinai's Regenerative Medicine Institute. Dhruv Sareen, PhD, director of the iPSC facility and a faculty research scientist with the Department of Biomedical Sciences, is the article's first author and one of several institute researchers who participated in the study.

"In these studies, we turned skin cells of patients who have ALS into motor neurons that retained the genetic defects of the disease," Baloh said. "We focused on a gene, C9ORF72, that two years ago was found to be the most common cause of familial ALS and frontotemporal lobar degeneration, and even causes some cases of Alzheimer's and Parkinson's disease. What we needed to know, however, was how the defect triggered the disease so we could find a way to treat it."

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Lou Gehrig's disease: From patient stem cells to potential treatment strategy in one study

Oct. 25, 2013 Although the technology has existed for just a few years, scientists increasingly use "disease in a dish" models to study genetic, molecular and cellular defects. But a team of doctors and scientists led by researchers at the Cedars-Sinai Regenerative Medicine Institute went further in a study of Lou Gehrig's disease, a fatal disorder that attacks muscle-controlling nerve cells in the brain and spinal cord.

After using an innovative stem cell technique to create neurons in a lab dish from skin scrapings of patients who have the disorder, the researchers inserted molecules made of small stretches of genetic material, blocking the damaging effects of a defective gene and, in the process, providing "proof of concept" for a new therapeutic strategy -- an important step in moving research findings into clinical trials.

The study, published Oct. 23 in Science Translational Medicine, is believed to be one of the first in which a specific form of Lou Gehrig's disease, or amyotrophic lateral sclerosis, was replicated in a dish, analyzed and "treated," suggesting a potential future therapy all in a single study.

"In a sense, this represents the full spectrum of what we are trying to accomplish with patient-based stem cell modeling. It gives researchers the opportunity to conduct extensive studies of a disease's genetic and molecular makeup and develop potential treatments in the laboratory before translating them into patient trials," said Robert H. Baloh, MD, PhD, director of Cedars-Sinai's Neuromuscular Division in the Department of Neurology and director of the multidisciplinary ALS Program. He is the lead researcher and the article's senior author.

Laboratory models of diseases have been made possible by a recently invented process using induced pluripotent stem cells -- cells derived from a patient's own skin samples and "sent back in time" through genetic manipulation to an embryonic state. From there, they can be made into any cell of the human body.

The cells used in the study were produced by the Induced Pluripotent Stem Cell Core Facility of Cedars-Sinai's Regenerative Medicine Institute. Dhruv Sareen, PhD, director of the iPSC facility and a faculty research scientist with the Department of Biomedical Sciences, is the article's first author and one of several institute researchers who participated in the study.

"In these studies, we turned skin cells of patients who have ALS into motor neurons that retained the genetic defects of the disease," Baloh said. "We focused on a gene, C9ORF72, that two years ago was found to be the most common cause of familial ALS and frontotemporal lobar degeneration, and even causes some cases of Alzheimer's and Parkinson's disease. What we needed to know, however, was how the defect triggered the disease so we could find a way to treat it."

Frontotemporal lobar degeneration is a brain disorder that typically leads to dementia and sometimes occurs in tandem with ALS.

The researchers found that the genetic defect of C9ORF72 may cause disease because it changes the structure of RNA coming from the gene, creating an abnormal buildup of a repeated set of nucleotides, the basic components of RNA.

"We think this buildup of thousands of copies of the repeated sequence GGGGCC in the nucleus of patients' cells may become "toxic" by altering the normal behavior of other genes in motor neurons," Baloh said. "Because our studies supported the toxic RNA mechanism theory, we used two small segments of genetic material called antisense oligonucleotides -- ASOs -- to block the buildup and degrade the toxic RNA. One ASO knocked down overall C9ORF72 levels. The other knocked down the toxic RNA coming from the gene without suppressing overall gene expression levels. The absence of such potentially toxic RNA, and no evidence of detrimental effect on the motor neurons, provides a strong basis for using this strategy to treat patients suffering from these diseases."

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Lou Gehrig’s disease: From patient stem cells to potential treatment strategy

Oct. 24, 2013 USC scientist Qi-Long Ying and a team of researchers have long been searching for biotech's version of the fountain of youth -- ways to encourage embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) to endlessly self-renew, or divide to produce more stem cells.

In a pair of studies published in Nature Communications in September and in The EMBO Journal in August, Ying and his team revealed some of the ways that ESCs and EpiSCs retain their pluripotency, or ability to differentiate into virtually any kind of cell.

The study in Nature Communications identified a novel way of culturing human ESCs by focusing on the Wnt/beta-catenin signaling pathway -- a group of molecules that work together to control various cell functions, including some related to embryonic development.

According to the researchers, this pathway can prompt mouse EpiSCs and human ESCs to either self-renew or differentiate. When the protein beta-catenin remains within the cell cytoplasm but outside of the nucleus, the stem cell continues to self-renew. When beta-catenin moves into a stem cell's nucleus, differentiation begins.

The paper published in The EMBO Journal addresses mouse ESCs, which are derived from the embryo at an earlier stage and are more pluripotent than mouse EpiSCs.

The study revealed the important role of Tfcp2l1 -- a transcription factor, or protein that controls which genes are turned on and off in a cell.

In mice, Tfcp2l1 helps communicate to ESCs that they should self-renew. The transcription factor also shows promise for "rewinding" slightly more differentiated EpiSCs into the more nave ESC state.

By learning more about the ESC and EpiSC playbooks, Ying and his colleagues can better control stem cell self-renewal, offering hope for patients with currently untreatable diseases and creating potential for a wide variety of other applications.

"These new findings have allowed us to develop conditions for the efficient propagation of human ESCs, and might also enable us to establish pluripotent stem cells from different species," said Ying, associate professor of stem cell biology and regenerative medicine at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. "This has far-reaching implications for a variety of applied areas of investigation, ranging from manipulating the genomes of agricultural animals to developing stem cell-based therapies for ailments such as Parkinson's disease or spinal cord injuries."

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Researcher reveals how to better master stem cells' fate

redOrbit Staff & Wire Reports Your Universe Online

For the first time, scientists from the Salk Institute for Biological Studies have taken stem cells from chimpanzees and bonobos and turned them into induced pluripotent stem cells (iPSCs), and their work has helped to highlight some of the differences between humans and non-human primates.

This type of cell, which has the ability to form any other type of cell or tissue in the body, can be used to model diseases that would normally be difficult to obtain from a living person or animal, the researchers said. The Salk Institute team, however, is using the iPSCs to compare and contrast the cells of humans with those of our closest living relatives the great apes with whom we share about 99 percent of our genome.

Comparing human, chimpanzee and bonobo cells can give us clues to understand biological processes, such as infection, diseases, brain evolution, adaptation or genetic diversity, senior research associate Iigo Narvaiza explained. Until now, the sources for chimpanzee and bonobo cells were limited to postmortem tissue or blood. Now you could generate neurons, for example, from the three different species and compare them to test hypotheses.

Narvaiza and senior staff scientist Carol Marchetto studied the iPSCs obtained from the great ape species. After comparing them to human stem cells, they discovered disparities in the regulation of so-called jumping genes or transposons DNA elements that can essentially copy and paste themselves into various locations in the genome between the two types of creatures.

These so-called jumping genes give scientists a way to quickly shuffle DNA, and could possibly be shaping the way in which our genomes evolve, the study authors said. They found genes that are differentially expressed between human iPSCs and similar cells from both chimpanzees and bonobos.

To the groups surprise, two of those genes code for proteins that restrict a jumping gene called long interspersed element-1, or L1 for short, the researchers reported. Compared with non-human primate cells, human iPSCs expressed higher levels of these restrictors, called APOBEC3B and PIWIL2.

L1 and a handful of other jumping genes are abundant throughout our genomes. Where these bits of DNA insert themselves is hard to predict, and they can produce variable effects. For example, they might completely disrupt genes, modulate them, or cause them to be processed into entirely new proteins, they added.

Using L1 that was tagged with a fluorescent marker, Narvaiza, Marchetto and their associates observed lower numbers of fluorescent iPSCs from humans than from non-human primates. In further research, the team produced iPSCs that had either too much or too little APOBEC3B and PIWIL2, and as they expected, elevated levels of those proteins hampered the mobility and reduced the appearance of DNA that had just been inserted into the ape cells.

These results suggested that L1 elements insert themselves less often throughout our genomes. Indeed, looking at genomes of humans and chimpanzees that had already been sequenced, the researchers found that the primates had more copies of L1 sequences than did humans, the Institute explained. The question that remains is, what would be the impact of differences in L1 regulation?

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Stem Cells Reveal Key Differences Between Apes And Humans

TORONTO, ON University of Toronto researchers have developed a method that can rapidly screen human stem cells and better control what they will turn into. The technology could have potential use in regenerative medicine and drug development. Findings are published in this weeks issue of the journal Nature Methods.

The work allows for a better understanding of how to turn stem cells into clinically useful cell types more efficiently, according to Emanuel Nazareth, a PhD student at the Institute of Biomaterials & Biomedical Engineering (IBBME) at the University of Toronto. The research comes out of the lab of Professor Peter Zandstra, Canada Research Chair in Bioengineering at U of T.

The researchers used human pluripotent stem cells (hPSC), cells which have the potential to differentiate and eventually become any type of cell in the body. But the key to getting stem cells to grow into specific types of cells, such as skin cells or heart tissue, is to grow them in the right environment in culture, and there have been challenges in getting those environments (which vary for different types of stem cells) just right, Nazareth said.

The researchers developed a high-throughput platform, which uses robotics and automation to test many compounds or drugs at once, with controllable environments to screen hPSCs in. With it, they can control the size of the stem cell colony, the density of cells, and other parameters in order to better study characteristics of the cells as they differentiate or turn into other cell types. Studies were done using stem cells in micro-environments optimized for screening and observing how they behaved when chemical changes were introduced.

It was found that two specific proteins within stem cells, Oct4 and Sox2, can be used to track the four major early cell fate types that stem cells can turn into, allowing four screens to be performed at once.

One of the most frustrating challenges is that we have different research protocols for different cell types. But as it turns out, very often those protocols dont work across many different cell lines, Nazareth said.

The work also provides a way to study differences across cell lines that can be used to predict certain genetic information, such as abnormal chromosomes. Whats more, these predictions can be done in a fraction of the time compared to other existing techniques, and for a substantially lower cost compared to other testing and screening methods.

We anticipate this technology will underpin new strategies to identify cell fate control molecules, or even drugs, for a number of different stem cell types, Zandstra said.

As a drug screening technology its a dramatic improvement over its predecessors, said Nazareth. He notes that in some cases, the new technology can drop testing time from up to a month to a mere two days.

Professor Peter Zandstra was awarded the 2013 Till & McCulloch Award in recognition of this contribution to global stem cell research.

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Predicting the fate of stem cells - Technique has potential use in regenerative medicine and drug development

PARIS: A woman who received a donor windpipe seeded with her own stem cells, is living healthily after the groundbreaking surgery five years ago, said a report in medical journal The Lancet.

"These results confirm what we, and many patients, hoped at the time of the original operation: that tissue engineered transplants are safe and effective in the long term," said Paolo Macchiarini who led the surgical team.

The journal hailed progress in tissue engineering when reporting the success of the surgery involving stem cells, which are immature cells that can 'grow' into specialised cells that can comprise and maintain the human body.

Donor windpipes are often rejected by the recipient's immune system, while patients also suffer the uncontrolled die-off of cells, called necrosis, and bleeding.

In the 2008 procedure performed on Claudia Castillo, the use of stem cells from the patient was tested to find out if the risk of attack by the immune system would be reduced.

The then 30-year-old woman who suffered from tuberculosis, received a new lease on life with the transplant that involved removing cells from a section of a donor windpipe and grafting cartilage cells grown from her own stem cells onto it.

Other cells taken from a healthy part of her windpipe were also used in the operation that saw the patient being discharged from hospital 10 days later.

The surgical team, led by Paolo Macchiarini from Stockholm's Karolinska University Hospital, could only determine the success of the operation through long-term follow-ups with the patient.

"The recipient continues to enjoy a good quality of life, and has not experienced any immunological complications or rejection of the implanted airway," said the findings published in The Lancet medical journal.

The report also noted that the patient continues to enjoy "a normal social and working life".

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Windpipe created from stem cells a success