BioUpdates for September, 2002

by Andrew Tolley

Giving Cells a Sense of Direction

Not Just Any Adult Stem Cell Will Do

Stroke of Luck

Wanted: Western Weed - Killer of Tumors

New Treatment Options Stemming For Diabetes

Giving Cells a Sense of Direction

One of the unanswered questions in embryonic development revolves around how developing cells organize themselves and get to where they must be in order to form a functioning organism. Now scientists from the University of Missouri and Vanderbilt University are providing clues that may lead to a more complete understanding of this process. Examining development in the zebrafish, the researchers have discovered a protein that facilitates cell migration in the embryo during gastrulation, the early stage of embryonic development. Comparing normal embryos to a mutant form called trilobites (because of the three-lobed shape of the mutated embryo), researchers discovered that the pattern of cell migration in the mutants was more chaotic, resulting in stunted development. These differences appear to be linked to the activity of a protein called Strabismus or Van Gogh, which has also been associated with development of wings and eyes in fruit flies. Further zebrafish investigation revealed that in the trilobite mutants, certain neurons did not migrate. Experiments involving the transplant of trilobite neurons into normal brains and vice versa confirmed these observations. In normal brains, transplanted trilobite neurons began to migrate, whereas normal neurons transplanted into the trilobite mutants did not migrate, suggesting that the presence and activity of the Strabismus or Van Gogh protein is crucial in facilitating normal embryonic development.

References:

Jessen, J.R. et al (2002). Zebrafish trilobite identifies new roles for Strabismus in gastrulation and neuronal movements. Nature Cell Biology.8 (Aug.): 610-615.

Visit:

Nature Cell Biology

http://www.nature.com/cgi-taf/DynaPage.taf?file=/ncb/journal/v4/n8/full/ncb828.html
Full text of the above article.

Vanderbilt University

http://exploration.vanderbilt.edu/news/features/zebrafish/news_zebrafish_feature.htm

Not Just Any Adult Stem Cell Will Do

Recent discoveries concerning adult stem cells have generated excitement among the research community, offering hope that the controversial issues surrounding embryonic stem cells can be bypassed. However, even more recently published articles may temper that excitement, suggesting that adult stem cells are neither as versatile as believed nor as potentially useful as hoped. A Stanford University research team examining adult blood-forming stem cells in mice failed to produce other tissue from these stem cells. After engineering a green fluorescent adult blood stem cell that could be tracked by microscope, the team introduced this cell into mice whose bone marrow had been eliminated. This cell was able to facilitate regeneration of the mice’s blood and immune cells, but there was a paucity of evidence to suggest this stem cell could facilitate the development of other tissue. Meanwhile, researchers at the Howard Hughes Medical Institute, working with neural crest stem cells in rats and chicks, are discovering that more care is required in identifying adult stem cells before they can be used therapeutically. It would appear from the research findings that adult stem cells are less versatile than fetal stem cells, and also that there can be different categories of stem cells within a particular type. The team’s findings indicate that there are at least two kinds of neural stem cell: those that give rise to central nervous system neurons and those that are responsible for peripheral nervous system cells. Logically, it is thus reasonable to suppose that any successful stem cell therapy would have to begin with identifying the appropriate type of stem cell. These studies do not necessarily mean adult stem cells are a scientific cul-de-sac but they do remind us that a lot more skillful navigation may be required.

References:

Wagers, Amy J. et al (2002). Little Evidence for Developmental Plasticity of Adult Hematopoietic Stem Cells. Science Express September 5th, 2002. Print version still to be published in Science.

Morrison, Sean J. et al (2002). Cell-Intrinsic Differences between Stem Cells from Different Regions of the Peripheral Nervous System Regulate the Generation of Neural Diversity. Neuron 35 (4) (Aug 15th): 643

Morrison, Sean J. et al (2002). Neural Crest Stem Cells Persist in the Adult Gut but Undergo Changes in Self-Renewal, Neuronal Subtype Potential, and Factor Responsiveness. Neuron 35 (4) (Aug 15th): 657

Visit:

Science/Science Express

http://www.sciencemag.org/cgi/content/abstract/1074807

Neuron

http://www.neuron.org/cgi/content/abstract/35/4/643
http://www.neuron.org/cgi/content/abstract/35/4/657

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Stroke of Luck

Scientists from the National Institute of Health’s Institute of Neurological Disorders and Stroke are uncovering compelling evidence for the effectiveness of a potential stroke vaccine. After examining the effect of the vaccine on rats genetically engineered to be prone to stroke, researchers are poised to begin clinical trials on people. The team hopes that this could be a major breakthrough in preventing one the top killers in the United States.

Because inflammation of the blood vessels is seen as a major factor contributing to strokes, the researchers investigated the role of a protein called E-selectin. This protein stimulates inflammation of blood vessels but also leads to lymphocytes (white blood cells) working to suppress inflammation. By creating an E-selectin-based vaccine the researchers hoped to create a heightened response from lymphocytes and thus reduce blood vessel inflammation. Testing their nasally administered vaccine on over 100 rats, the researchers have compiled strong evidence that an E-selectin vaccine has great potential. Over the course of a year’s study, rats given repeated doses of the vaccine had 16 times fewer ischemic strokes than rats in a control group, and no vaccinated rats suffered hemorrhagic strokes. What is more, in those rats that did suffer strokes the extent of brain damage was considerably reduced. Observations indicate that the lymphocytes from the vaccinated rats produced cytokines that blocked the inflammation of blood vessels. The very encouraging results lay the foundation for clinical trials on people at high risk for stroke, using human and bovine E-selectin vaccines.

References:

Takeda, H. et al (2002). Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats. Stroke: Journal of the American Heart Association. Vol. 33 #9 (Sept. 2002): 2156-2164

Visit:

Stroke: Journal of the American Heart Association

http://stroke.ahajournals.org/cgi/content/full/33/9/2156
Full article of the above reference.

Wanted: Western Weed - Killer of Tumors

Medulloblastoma is an aggressive brain cancer in children. Research has established that the development of medulloblastoma tumors is associated with the continued activation of the "hedgehog" pathway by the interactions of the "Patched" gene and "Smoothened" protein. In embryonic development this pathway is key to cell differentiation, but if mutations allow continued activation, cancerous tumors can result. Armed with this understanding, a research team from the Howard Hughes Medical Institute has been investigating how a chemical compound, cyclopamine can block the "hedgehog" pathway. Cyclopamine is derived from a western weed Veratrum californicum (commonly known as the corn lily). In previous work on mouse embryos the team demonstrated that cyclopamine blocked the pathway. They subsequently began to explore whether it could do the same in tumors. Their reasoning proved to be correct -- tests on mice demonstrated that cyclopamine could prevent the development of tumors as well as halt and reverse the growth in existing tumors without any evident side effects. Further work on surgically removed human medulloblastoma tumors produced similar results. Lead researcher Phillip A. Beachy believes there is now sufficient evidence to commence clinical testing in humans. Unfortunately, obtaining an adequate supply of cyclopamine will be a major challenge if cyclopamine becomes established as an effective therapy. Extraction and purification of cyclopamine from Veratrum californicum is unlikely to yield a sufficient amount; synthesis from alternative sources will almost certainly be necessary.

References:

Beachy, Phillip A. et al (2002). Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade. Science 297 (Aug 30th): 1559

Visit:

Science

http://www.sciencemag.org/cgi/content/full/297/5586/1559
Full text of above article.

New Treatment Options Stemming For Diabetes

At the root of both type 1 and type 2 diabetes is the depletion or compromised function of pancreatic beta cells. Either a lack of these cells or their inability to secrete sufficient insulin leads to the failure of the body to regulate blood glucose levels. Discovering ways to provide functioning pancreatic beta cells is one avenue being explored by researchers to combat diabetes. Researchers from Massachusetts General Hospital (MGH) are reporting progress in this field. The MGH research team has already demonstrated in clinical trials that a naturally occurring intestinal hormone, glucagon-like peptide 1, can stimulate beta cells to proliferate and secrete insulin. Now the team also has evidence that the hormone can stimulate islet stem cells, (nestin-positive islet-derived progenitor cells) to develop into mature insulin secreting pancreatic beta cells. It appears that a receptor protein expressed by the stem cells binds with the hormone that in turn induces the stem cell to differentiate into the beta cells. In short, the MGH work is opening up a new avenue of diabetes treatment. Generating new beta cells for transplantation from a patient’s own islet stem cells reduces the risk of rejection and avoids the ethically sensitive issue of embryonic stem cell use.

References:

Habener, Joel et al (2002). Insulinotropic Hormone Glucagon-Like Peptide-1 Differentiation of Human Pancreatic Islet-Derived Progenitor Cells into Insulin-Producing Cells. Endocrinology 143 (Aug): 3152

Visit:

Endocrinology

http://endo.endojournals.org/cgi/content/abstract/143/8/3152
Abstract of above reference.

Massachusetts General Hospital

http://www.mgh.harvard.edu/depts/pubaffairs/releases/030101pancreas.htm
Release on earlier research leading to current discovery.