NYAM Symposium Written Up in BioMedNet News

Nerve stem cells show a degree of commitment

Reprinted with permission from BioMedNet News, an Elsevier Science publication

by Apoorva Mandavilli, BioMedNet News

Rather than the pluripotent cells they are thought to be, stem cells in the peripheral nervous system may be intrinsically programmed to become specific kinds of cells in specific environments, according to unpublished results revealed today. "We can't any longer just think of stem cells as a blank slate," lead investigator Sean Morrison told BioMedNet News. Instead, he says, different classes of the neural crest stem cells, in combination with the different environments of the nervous system, generate the diverse population of neural cells.

Morrison, who is assistant professor of cell and developmental biology at the University of Michigan, presented his results at a two-day symposium on Cell and Tissue Engineering, sponsored by the New York Academy of Medicine. Neural crest stem cells (NCSCs) can either undergo self-renewal, form neurons and glia of the peripheral nervous system, or develop into other tissues like vascular smooth muscle. Morrison and his colleagues have previously shown that the bone morphogenetic protein BMP2 instructs NCSCs to become neurons, while the Notch ligand Delta induces rapid differentiation into glia. On day 14 of rat embryo development, NCSCs are present in both the gut and the sciatic nerve, and are capable of forming both neurons and glia. But, notes Morrison, the stem cells in the gut form neurons, while those in the sciatic nerve form glia.

To evaluate the relative role of the environment and the stem cells themselves in determining their fate, the researchers isolated NCSCs from the two locations on day 14.

Stem cells derived from the gut are 5- to 10-fold more sensitive to the effects of the neurogenic BMP2 than those from the sciatic nerve, the researchers found. Even after 8 days of culture, the cells retained their increased sensitivity to BMP2, suggesting that the difference is stably encoded within the stem cells.

But, the cells are not "committed progenitors," Morrison pointed out. For example, in Remak's ganglia, found in birds, stem cells from the sciatic nerve can differentiate into neurons. Still, he says, over short intervals, neural crest stem cells in different locations preferentially become specific kinds of cells. These results have not yet been submitted for publication. Morrison and his colleagues are now engaged in isolating the differences between the stem cells at a molecular level, using large microarray studies. More than 90% of the impact of stem cells will be from their use as tools rather than as therapies, predicts John W. McDonald, director of the spinal cord injury unit at Washington University in St. Louis. McDonald himself is using embryonic stem cells to repair injury sites in a rat model of spinal cord injury.

McDonald's previous publications on the subject are "very important," and his work is crucial in understanding "how embryonic stem cells can improve regeneration after injury," Morrison told BioMedNet News. McDonald and his colleagues injected stem cells into the rat spinal cord 9 days after injury, when it most closely resembles spine injury in human patients. Five weeks after injection, 60% of the cells had differentiated into oligodendrocytes, 30% into astrocytes, and less than 10% into neurons. Each of the oligodendrocytes wraps around 20-40 axons, as in normal rats, the researchers found. Although the cells show abnormal reorganization, common in such transplants, there is vascularization, and clinically significant behavioral change, McDonald says.

"Our presumption is the improvement is due to remyelination," of axons by the dendrocytes, McDonald said. "We haven't proven it yet, but we are working toward it." To prove that the improvement in function is due to remyelination of the injured axons, McDonald's team is now performing experiments with antisense mRNA to inhibit myelination.

Although scientists have shown correlations between specific treatments and restoration of function, "no one has been able to prove that any cellular or pharmacological treatment improves cellular function," McDonald explained. If their experiments succeed, he said, it will be "the best that science has done so far."

Bioengineers make a whole new kind of heart pill 12 March 2002 16:25 EST Reprinted with permission from BioMedNet News, an Elsevier Science publication by Apoorva Mandavilli, BioMedNet News

In the first of many steps toward building a "heart in a box," Canadian scientists have succeeded in inducing the formation of new blood vessels. Their tools? Genetically engineered cells encased in the material from a soft contact lens. Although it may take scientists 10 to 20 years to build an entire heart, growing functional blood vessels is "a first step to growing larger organs," said Michael Sefton, who directs the institute of biomaterials and biomedical engineering at the University of Toronto. He was speaking today at a two-day symposium on Cell and Tissue Engineering, sponsored by the New York Academy of Medicine.

Sefton and his colleagues from across the world formed The Living Implants From Engineering Initiative, a ten-year, $5 billion, international collaboration of scientists, in 1998. Their first project is to create an engineered heart. En route, the scientists must master methods to provide the cells with enough nutrition, grow heart valves, pacemaker cells, and blood vessels to connect to the host blood supply.

In many cases, what is needed is only a certain piece of the heart, such as a pediatric valve, rather than the whole heart, says Sefton. The only difference between growing tissues and entire organs is their size, he says. To solve the need for blood supply to the tissue, the researchers genetically engineered mouse fibroblasts to produce vascular endothelial growth factor (VEGF), which stimulates blood vessel formation. The cells are encapsulated in a biocompatible polymer membrane called HEMA-MMA, used in soft contact lenses; the polymer is permeable to small molecules such as glucose and other nutrients, but impermeable to larger molecules that would cause rejection. A few days after they implanted the cells in mice, the researchers observed new blood vessels. They are currently trying to quantify the number of new blood vessels.

However, "the major issue may not be the growth of the blood vessels," Sefton said. "The crucial question we need to address is whether they are functional." If the blood vessels are leaky, for example, they might not carry blood at a high enough flow rate, he explains. Sefton estimates that within a few months, his team will have quantified vessel formation, and within the year, will have established functional blood vessels.

Sefton's approach is "really innovative," Johns Hopkins University biomedical engineer Kam Leong told BioMedNet News. If the researchers succeed, the work will have "profound implications in the management of wound healing," he said. The research is still in "very early days," Sefton admitted. Blood vessel development requires multiple growth factors, so the researchers may need to engineer cells to deliver more than one angiogenic growth factor. They must also compile information on specific concentrations of the required molecules, time of exposure, and the order in which the molecules should be released. Eventually, such cells would be implanted along with capsules expressing a protein of interest, such as insulin for the treatment of diabetes, dopamine in Parkinson's disease, or other genetically modified cells for gene therapy, Sefton says. Such cells must be able to secrete proteins, while remaining protected from the immune system.

But the researchers are yet to succeed on that front. Although the encapsulated cells are resistant to the immune system, they succumb to activated macrophages.

Posted on March 11, 2002

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