Immune System Helps Transplanted Stem Cells Navigate in CNS

UCI study provides blueprint for enhanced treatment of inflammatory diseases like MS 
Wednesday, 02 June 2010

By discovering how adult neural stem cells navigate to injury sites in the central nervous system, UC Irvine researchers have helped solve a puzzle in the creation of stem cell-based treatments: How do these cells know where to go?

Tom Lane and Kevin Carbajal of the Sue and Bill Gross Stem Cell Research Center found the answer with the body's immune system.

Their study not only identifies an important targeting mechanism in transplanted stem cells but also provides a blueprint for engineering stem cell-based therapies for multiple sclerosis and other chronic neurological diseases in which inflammation occurs. Results appear in this week's early online edition of the Proceedings of the National Academy of Sciences.

"Previously, we've seen that adult neural stem cells injected into the spinal column knew, amazingly, exactly where to go," said Lane, Chancellor's Fellow and professor of molecular biology & biochemistry.

"We wanted to find what directed them to the right injury spots."

The researchers used adult neural stem cells to treat mice with a disease similar to MS that destroys myelin, the protective tissue coating on nerves, causing chronic pain and loss of motor function. Adult neural stem cells have shown the ability to change – or differentiate – into oligodendrocytes, the building blocks of myelin, and repair or replace affected tissue.

In the mice, inflammatory cells – reacting to the virally induced nerve damage – were observed activating receptors on the adult neural stem cells. These CXCR-4 receptors, in turn, recruited chemokine proteins called CXCL-12 that guided the stem cells to specific sites. Chemokines are produced in acute and chronic inflammation to help mobilize white blood cells.

As the stem cells migrated through the central nervous system, they began to transform into the precursor cells for oligodendrocytes. Latching onto their repair sites, they continued the differentiation process. Three weeks after the initial treatment, 90 percent of the cells had grown into fully formed oligodendrocytes.

In earlier work, Lane and colleagues demonstrated that adult neural stem cell treatments improved motor function in mice with chronic MS symptoms.

"In this study, we've taken an important step by showing the navigational cues in an inflammatory environment like MS that guide stem cells," said Lane.

"Hopefully, these cues can be incorporated into stem cell-based treatments to enhance their ability to repair injury."

Chris Schaumburg and Joy Kane of UCI and Dr. Robert Strieter of the University of Virginia participated in the study, which received support from the National Institutes of Health and the National Multiple Sclerosis Society.

Lane recently received a Collaborative MS Research Center Award from the National Multiple Sclerosis Society to assemble a team to investigate the use of cell replacement therapy to regenerate MS-ravaged nerve tissue.
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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/

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Jumping Genes Provide Extensive 'Raw Material' for Evolution

Jumping Genes Provide Extensive 'Raw Material' for Evolution
Wednesday, 02 June 2010

Using high-throughput sequencing to map the locations of a common type of jumping gene within a person's entire genome, researchers at the University of Pennsylvania School of Medicine found extensive variation in these locations among the individuals they studied, further underscoring the role of these errant genes in maintaining genetic diversity.

The investigators determined that any two peoples' genomes differ at roughly 285 sites out of the 1139 sites studied. These results were found by scanning the genomes of 25 individuals, 15 of which were unrelated. They report their findings online in Genome Research.

Jumping genes – also called transposons – are sequences of DNA that move to different areas of the genome within the same cell.

"The significance of this work is that there is much more diversity in our genome due to insertions by this family of transposons than previously thought," said co-author Haig Kazazian, MD, Seymour Gray Professor of Molecular Medicine, in the Penn Department of Genetics.

"This movement of genetic material provides the raw material of genetic evolution, and it doesn't take into account the insertions that we believe occur outside of the sperm and egg cells studied in this project."

Transposons are a source of diversity within a species' gene pool, with implications on many levels. For example, slight changes in genes help organisms adapt and survive in new environments, and populations with genetic diversity are less vulnerable to disease and problems with reproduction.

Insertions into certain spots in the genome can also cause cell function to go awry, so understanding their placement and variation in the human genome is important for a fundamental understanding of disease. Insertions can cause many genetic diseases, such as haemophilia and Duchenne muscular dystrophy, and may play a role in the development of cancer.

Retrotransposons are the major class of jumping genes, with the L1 family the most abundant type of retrotransposon in the human genome. L1s comprise about 17 percent of the human genome and were the subject of this study.

Eventually, continuous jumping by retrotransposons expands the size of the human genome and may cause shuffling of genetic content. For example, when retrotransposons jump, they may take portions of nearby gene sequences with them, inserting these where they land, and thereby allowing for the creation of new genes. Even otherwise unremarkable insertions of L1s may cause significant effects on nearby genes, such as lowering their expression.

Retrotransposons move by having their DNA sequence transcribed or copied to RNA, and then instead of the genetic code being translated directly into a protein sequence, the RNA is copied back to DNA by the retrotransposon's own enzyme called reverse transcriptase. This new DNA is then inserted back into the genome. The process of copying is similar to that of retroviruses, such as HIV, leading scientists to speculate that retroviruses were derived from retrotransposons.

The team also found that on average 1 in 140 individuals have obtained a new L1 insertion from their parents. When all retrotransposon insertions, including L1 and others, are considered about 1 in 40 individuals have received a new insertion from their parents.

The current study counted insertions in the heritable germ cell line, which is in egg and sperm cells.

"The real elephant in the room is the question of the incidence of somatic insertions, insertions in cells that aren't eggs or sperm" says Kazazian.

"We don't yet know the incidence of those somatic insertions."

Because the insertions detected in this study and others like it are present in some individuals and not others, there is the possibility of association with genetic disease. Future studies in the Kazazian lab funded by an ARRA stimulus grant through the National Institutes of Health will develop techniques to uncover such associations using these retrotransposon insertions as genetic markers.
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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/

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Breakthrough in Stem Cell Culturing

Method developed for culturing large quantities of human embryonic stem cells under completely chemically controlled conditions
Tuesday, 01 June 2010

For the first time, human embryonic stem cells have been cultured under chemically controlled conditions without the use of animal substances, which is essential for future clinical uses. The method has been developed by researchers at Karolinska Institute and is presented in the journal Nature Biotechnology.

Embryonic stem cells can be turned into any other type of cell in the body and have potential uses in treatments where sick cells need to be replaced. One problem, however, is that it is difficult to culture and develop human embryonic stem cells without simultaneously contaminating them. They are currently cultured with the help of proteins from animals, which rules out subsequent use in the treatment of humans. Alternatively the stem cells can be cultured on other human cells, known as feeder cells, but these release thousands of uncontrolled proteins and therefore lead to unreliable research results.

A research team at the Department of Medical Biochemistry and Biophysics, Karolinska Institute has now managed to produce human stem cells entirely without the use of other cells or substances from animals. Instead they are cultured on a matrix of a single human protein: laminin-511.

"Now, for the first time, we can produce large quantities of human embryonic stem cells in an environment that is completely chemically defined," says professor Karl Tryggvason, who led the study.

"This opens up new opportunities for developing different types of cell which can then be tested for the treatment of disease."

Together with researchers at the Harvard Stem Cell Institute, the researchers have also shown that in the same way they can culture what are known as reprogrammed stem cells, which have been converted back from tissue cells to stem cells.

Laminin-511 is part of our connective tissue and acts in the body as a matrix to which cells can attach. In the newly formed embryo, the protein is also needed to keep stem cells as stem cells. Once the embryo begins to develop different types of tissue, other types of laminin are needed.

Until now, different types of laminin have not been available to researchers, because they are almost impossible to extract from tissues and difficult to produce. Over the last couple of decades, Karl Tryggvason’s research group has cloned the genes for most human laminins, studied their biological role, described two genetic laminin diseases and, in recent years, even managed to produce several types of laminin using gene technology. In this latest experiment, the researchers produced the laminin-511 using recombinant techniques.

Reference:
Long-term self-renewal of human pluripotent stem cells on human recombinant laminin-511
Sergey Rodin, Anna Domogatskaya, Susanne Ström, Emil M Hansson, Kenneth Chien, José Inzunza, Outi Hovatta, Karl Tryggvason
Nature Biotechnology, online 30 May 2010, doi: 10.1038/nbt.1620
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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/

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