Don’t Go Changing: New Chemical Keeps Stem Cells Young

Scientists at the Universities of Bath and Leeds have discovered a chemical that stops stem cells from turning into other cell types, allowing researchers to use these cells to develop new medical treatments more easily.

Stem cells have the ability to develop into many other cell types in the body, and scientists believe they have huge potential to treat diseases or injuries that don’t currently have a cure.

Professor Melanie Welham’s team at the University of Bath’s Department of Pharmacy & Pharmacology, collaborating with Professor Adam Nelson at the University of Leeds, have discovered a chemical that can be added to embryonic stem cells grown in the lab, allowing them to multiply without changing into other cell types.

This breakthrough will help scientists produce large stocks of cells that are needed for developing new medical therapies.

Professor Welham, who is co-director of the University of Bath’s Centre for Regenerative Medicine, explained: “Stem cells have great potential for treating spinal injuries and diseases like type I diabetes because they can change into a range of specialised cell types including nerve or pancreatic cells, which could be used to repair damaged tissues.

“Unfortunately, when you grow stem cells in the lab, they can spontaneously develop into specialised cells, making it difficult to grow large enough stocks to use for medical research.

“We’ve identified a chemical that will put this process on hold for several weeks so that we can grow large numbers of them in their unspecialised state. This is reversible, so when you take it away from the cells, they still have the ability to change into specialised cells.”

Professor Adam Nelson’s team, at the Astbury Centre for Structural Molecular Biology, made more than 50 chemical compounds that were tested for activity in the stem cells.The researchers found that the chemicals worked by blocking an enzyme, called GSK3, that can control when the stem cell switches to a more specialised cell type.

Professor Nelson, who is Director of the Astbury Centre at the University of Leeds, said: “This research is a great example of how small molecules can be used as tools to understand biological mechanisms.”

The research, supported by funding from the Biotechnology & Biological Sciences Research Council.

Gene Mutations Increase Risk For Aggressive Prostate Cancer

Men who develop prostate cancer face an increased risk of having an aggressive tumor if they carry a so-called breast cancer gene mutation, scientists from the Albert Einstein College of Medicine of Yeshiva University report in the January 29 issue of Clinical Cancer Research. The findings could help to guide prostate-cancer patients and their physicians in choosing treatment options.

The study, involving 979 men with prostate cancer and 1251 men without the disease, looked at whether participants carried mutations for either of two genes, BRCA1 and BRCA2. Women carrying mutations in either gene face an increased risk of developing breast cancer, ovarian cancer, or both.

All the people enrolled in the Einstein study were of Ashkenazi Jewish descent. The study focused on them because they are five times likelier than people in the general population to carry a mutation of any kind in the BRCA1 or BRCA2 genes. The researchers looked for the presence of three particular mutations–two in BRCA1 and one in BRCA2. Scientists believe that genetic discoveries among the Ashkenazi can benefit society as a whole in terms of preventing and treating major diseases.

Having any of the three mutations did not increase a man's risk of developing prostate cancer, the study found. But for those men who did develop prostate cancer, two of the mutations–BRCA1-185delAG and the mutated BRCA2 gene–increased the risk that tumors would be aggressive or high-grade, as defined by a Gleason score of 7 or above. The Gleason score, based on the microscopic appearance of prostate tissue removed during a biopsy or surgery, assesses the aggressiveness of a prostate tumor on a scale from 2 (least aggressive) to 10 (most aggressive).

Specifically, prostate cancer patients with high-grade, aggressive tumors (Gleason scores of 7 or above) were 3.2 times more likely to carry the BRCA2 gene mutation than were men in the control group. Carriers of the BRCA1-185delAG mutation were also at increased risk of having an aggressive prostate cancer.

Previous investigations into a possible link between prostate-cancer risk and the BRCA1 and BRCA2 genes have yielded conflicting results–perhaps because they involved small numbers of subjects and lacked well-matched control groups. "Our large study shows conclusively that prostate cancer patients with either the BRCA2 gene mutation or the BRCA1-185delAG mutation are more susceptible to aggressive cancers than people without that mutation," says Robert Burk, M.D., professor of pediatrics (genetics) at Einstein and senior author of the study.

Routine genetic testing for BRCA mutations–done by analyzing blood samples or cells swabbed from the inside of one's cheeks–wouldn't be justified for most men, says Dr. Burk: the prevalence of the mutations in the general population is very low; and men with high Gleason scores already know that their prostate cancer is aggressive. But, notes Dr. Burk, "our findings might have practical implications for some men diagnosed with early-stage (low Gleason score) prostate cancers–particularly Ashkenazi Jewish men, who are much more likely to have these mutations."

"One of the biggest problems with early-stage prostate cancer is being able to distinguish between tumors with the potential to become aggressive and those that may persist for many years without enlarging or spreading," notes Dr. Burk. For that reason, he says, Ashkenazi men diagnosed with early-stage prostate cancer might want to consider getting tested for the BRCA2 and BRCA1-185delAG mutations.

Knowing they have the mutation—and that their tumor may become aggressive—may influence treatment options that patients pursue. For example, a prostate cancer patient who has the BRCA2 mutation might vote against 'watchful waiting'—in which the growth of the cancer is monitored and treatment is held in abeyance—and instead opt for surgery or radiation treatments with or without hormone blockade therapy.

For early-stage prostate cancer patients in the general population, knowing they carry the BRCA1 or BRCA2 mutation would also be useful, says Dr. Burk. But these mutations are so rare in the general population—a prevalence of far less than one percent—that testing is unlikely to reveal their presence.

Other Einstein researchers involved in the study were Dr. Ilir Agalliu and Suzanne Leanza. The authors have no potential conflicts of interest relevant to this article.

Mesh-like Network Of Arteries Adjusts To Restore Blood Flow To Stroke-injured Brain

A grid of small arteries at the surface of the brain redirects flow and widens at critical points to restore blood supply to tissue starved of nutrients and oxygen following a stroke, a new study has found.

“This is optimistic news,” said David Kleinfeld, a physics professor at the University of California, San Diego, whose group studies blood flow in animal models of stroke.

Damage from stroke can continue for hours or even days as compromised brain tissue surrounding the core injury succumbs to deprivation of oxygen and nutrients.

“This is the area doctors are trying to protect after a stroke,” said Andy Shih, a postdoctoral fellow in Kleinfeld’s group who conducted the experiments. “Those neurons are teetering on the edge of death and survival.”

Previous work with animal models had found that blood flow can persistently slow in the aftermath of a stroke, which would hinder the delivery of drugs that might help recovery. But those studies only measured the speed of the blood.

By measuring both the speed of blood cells moving through individual small arteries and the diameters of the same vessels, the scientists found that the arteries dilate to maintain a constant delivery of blood cells.

“You find that the velocity has gone down, but that the diameter—on average—exactly compensates,” Kleinfeld said.

Patrick Drew and Philbert Tsai in Kleinfeld’s group, and Beth Friedman and Patrick Lyden, MD, of the neuroscience department at UC San Diego’s School of Medicine co-authored the paper. Lyden, whose contributions to a 1995 study proved that the drug tPA can reverse the course of stroke when administered promptly, also directs the UC San Diego Stroke Center. The Journal of Cerebral Blood Flow and Metabolism published their new finding online January 28.

Key to this resilience, it seems, is the structure of the vascular network overlying the brain.

“Vessels on the surface of the brain have a mesh-like architecture,” Kleinfeld said. “One consequence of that is that it operates like a grid system that redistributes “current flow as you need it.”

“City traffic freezes a lot less than you would think because once a street gets bogged down, you can move over to another street,” he said. “This seems to be what happens on the surface of the brain.”

Flows through the surface vessels reversed and stalled, as previously observed, but those changes helped to redistribute blood to ensure a steady supply though vessels that penetrate into the brain.

Shih focused his measurements on small arteries, called arterioles, at the point where they dive into the brain to supply a discrete patch of the cortex, a juncture that is vulnerable to occlusions that can cause microstrokes this group’s previous work has found.

“These are extremely important. A single penetrating arteriole will feed a column of tissue,” Shih said. “These are bottlenecks in flow.”

The penetrating vessels neither reversed nor stalled, even though many connected to loops and bridges in the vascular network that could have allowed that to happen. Even when the pressure dropped permanently as a result of stroke damage, wider lanes allowed the network to deliver red blood cells at the same rate.

“Diameter is the major determinant to how blood actually flows through vessels. Open up a blood vessel a little bit and you’ll have a huge change in the amount of blood that goes through,” Shih said. “Blood flow comes back, and it seems that these vessels are very resistant to the stroke. They function quite normally.”

The work was funded by the Canadian Institutes of Health Research, National Institutes of Health, National Science Foundation and Veterans Medical Research Foundation.