Lung airway stem cells awry in cystic fibrosis

Recent research from the University of Iowa suggests that people with cystic fibrosis have fewer of the stem cells that would normally repair the airway.

In most people, glands in the airway secrete bacteria-killing factors to help fight infection. These glands are also home to airway stem cells that rebuild the glands and keep them functioning normally. The Iowa team found that in people with CF, the airway stem cells had packed up and moved to the surface of airway rather than being nestled in the protective glands.

The team didn’t find a clear cause and effect, but they suggest that with fewer airway stem cells, those glands are less able to repair themselves and secrete factors to help ward off infection. John Engelhardt, Roy J. Carver Chair in Molecular Medicine and professor and head of anatomy and cell biology who led the research, suggests that the next step might be to learn how to manipulate the environment, or stem cell niche, of those glands so that the stem cells will stay put and keep the glands functioning properly. Such a therapy could help prevent the infections that wreak such havoc on people with CF.

A University of Iowa press release quotes Engelhardt:

“This is the first demonstration that lung stem cell niches may be altered in CF.” … “The future excitement of these findings relates to the potential of manipulating lung stem cells through neuropeptides or their inhibitors.”

The work was published in the July 18 issue of July 18 issue of Journal of Clinical Investigation.

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Tracking stem cells using tricks learned in outer space

Stem cell science is set to get a boost from an unlikely source: outer space. It turns out that techniques devised to help telescopes peer through the blur of the earth’s atmosphere could help scientists peak more deeply into tissues. If the technique, called adaptive optics or AO, works it might prove useful for scientists hoping to track the whereabouts of transplanted stem cells.

A group of researchers at the University of California, Santa Cruz, including CIRM grantee Joel Kubby, have formed the W. M. Keck Center for Adaptive Optical Microscopy, which will apply AO techniques to microscopes built for peering deep into tissues.

A press release from UCSC describes the project:

Principal investigator Joel Kubby, an associate professor of electrical engineering in the Baskin School of Engineering at UCSC, has worked on adaptive optics (AO) systems for large telescopes as well as for biological imaging. In astronomy, AO systems correct the blurring of telescope images caused by turbulence in the Earth’s atmosphere. In microscopy, blurring is caused by the flowing cytoplasm of living cells.

“We can get beautiful images of cells close to the surface of the tissue, but if you want to go deep you’re out of luck because of the degradation of the image. That was the motivation for this project,” said co-investigator William Sullivan, professor of molecular, cell, and developmental biology at UC Santa Cruz. “For cell biologists, anything that improves imaging is a big deal, and this has the potential to open up vast areas of cell biology that have been opaque to us.”

In stem cell research, for example, an important bottleneck in efforts to develop stem cell therapies has been the inability to follow injected stem cells and monitor their fates below the surface of the tissue. AO microscopy could solve this problem, and the California Institute for Regenerative Medicine (CIRM) has provided support for the work at UCSC, including funding that led to the development of the team’s first AO microscope.

Knowing where a stem cell goes once it has been transplanted is critical to developing new therapies. Unless they go to where the damage is and stay there, those cells won’t hold any long-term therapeutic benefit. Tracking cells within tissues could point to better ways of transplanting the cells and, eventually, to more effective therapies.

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A history of the stem cell lawsuit & what it meant to California scientists

Today U.S. District Judge Royce Lamberth dismissed a lawsuit that has been creating uncertainty for stem cell scientists for almost a year. The Washington Post quotes Lamberth’s opinion:

“This Court, following the D.C. Circuit’s reasoning and conclusions, must find that defendants reasonably interpreted the Dickey-Wicker Amendment to permit funding for human embryonic stem cell research because such research is not ‘research in which a human embryo or embryos are destroyed,’ ” Lamberth wrote.

Here’s some history on the lawsuit from this blog:

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Discoverer of brain stem cells becomes president of ISSCR

The North County Times had a good story yesterday about Fred Gage’s new role as the president of the International Society for Stem Cell Research. Gage is a renowned stem cell scientists at The Salk Institute for Biological Studies, which also wrote about his new role.

Gage was the first to show that people do, in fact, produce new brain cells after birth. In work that is especially close to my heart, he also showed that mice that get (to quote the 1999 press release) “regular voluntary exercise on running wheels” also grow more brain cells than sedentary mice.

More recently, Gage has had CIRM funding to carry out studies modeling human neurological diseases in a lab dish as a way of understanding and treating those diseases. We’ve blogged about his work here and here.

As the new president of ISSCR, which represents about 4,000 stem cell scientists internationally, Gage said he hoped to advocate for stem cell science to the public and to politicians. He also hopes to advance ISSCR’s mission of moving basic stem cell discoveries into clinical therapies. He told the North County Times:

“There’s been a lot of fantastic basic research that has been done,” Gage said. “We realize that part of our mission as a society is to translate these basic science into clinical applications. We call it bench to bedside. We’re thinking about ways to do this most effectively.”…

“You have to have the basic biologists helping in this, but we need the clinicians too, even though they don’t have the (scientific) knowledge,” Gage said. “We need to bring them up to speed. And underlying all this, we need to have a very effective fundraising effort for the society.”

Gage talked to CIRM about how stem cells can be used to mimic disease in a lab dish:

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Aggressive breast cancer treated with bone marrow stem cells

Last week brought a paper by Stanford researchers that has been a long, long time coming. It shows that 12-14 years after the experimental treatment, women with metastatic breast cancer benefited from high dose chemotherapy followed by transplantation of their own blood-forming stem cells. The paper was published online July 15 in Biology of Blood and Marrow Transplantation.

Back at the time when the group, which included CIRM grantee Irv Weissman, carried out this trial, doctors were rejecting high-dose chemotherapy for people with metastatic breast cancer. That therapy destroys the cancer, but also destroys the patient’s bone marrow, which produces all blood and immune cells. That side effect would be deadly, but doctors can reinject bone marrow cells taken from patients before chemotherapy. This is the process that is used today for many types of cancers. However, doctors were finding that the whole bone marrow also contained some breast cancer cells. If those cells survived the transplantation they could spread and form a new, deadly cancer. So much for the chemotherapy.

Back when the Stanford scientists carried out their trial (between 1996 to 1998) Weissman had recently figured out how to purify the blood-forming stem cells in the bone marrow that are responsible for rebuilding the blood system. He and the team thought they could pull out just those cells from the patient’s blood and use those cells to save the blood system after high-dose chemotherapy. If it worked, the chemotherapy would destroy the cancer, and the purified stem cells would save the blood system without reintroducing cancer cells lurking in the blood.

It all sounded good, but they were not sure whether their idea had worked until now. What they learned is that 23 percent of the women in their trial are still alive, compared to 9 percent of women who received unpurified stem cells.

A Stanford press release about the work quotes Weissman:

“Even with this small sample size, this paper demonstrates much-better overall and progression-free survival in those patients who received cancer-free stem cells.”

Senior author on the paper Judith Shizuru said in the release:

“Most people in the oncology community feel that this issue is a done deal, that high-dose chemotherapy does not work for patients with breast cancer. But our study suggests that the high-dose therapy strategy can be modified to include the use of cancer-free purified blood stem cells to yield better overall outcomes in women with advanced breast cancer.”

The authors are encouraging scientists to revisit high-dose chemotherapy for other cancers where it isn’t traditionally offered. If it shows benefit for those patients it could open up a new form of therapy for a wide range of cancers.

This paper also highlights something that will continue to be true of all forms of stem cell research: It takes a long time to learn whether a therapy was truly effective. A decade from now we’ll know whether the stem cell trials of today really worked. It’s slow and frustrating, but papers like this one make the wait worth while.

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CIRM Bridges to Stem Cell Research students talk science in our new video

On July 8, 2011 the CIRM Bridges to Stem Cell Research trainees met in Burlingame, CA to share results from their research internships. Their enthusiasm for stem cell science made for a fun poster session where the students had a chance to share their internship research with other students, with CIRM staff and board members, and with California stem cell scientists who attended.

This video gives an overview of what these students have been up to:

First established in 2009, the Bridges programs fund students at community colleges and California State schools to take stem cell classes and do internship projects in established stem cell research labs in industry or at University of California and other major university campuses. (This map shows the Bridges to Stem Cell Research programs in purple.) Given the expense of working with stem cells, students at these schools would likely never have had a chance to participate in this cutting edge research. And without that experience, these students would likely be shut out of careers in California’s growing stem cell industry. 

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Guest blogger Alan Trounson — July’s stem cell research highlights

Each month CIRM President Alan Trounson gives his perspective on recently published papers he thinks will be valuable in moving the field of stem cell research forward. This month’s report, along with an archive of past reports, is available on the CIRM website.

In the past month one paper struck me as especially important because it has the potential to alleviate a particularly nasty disability. Radiation therapy can buy time for patients with brain tumors, but the collateral damage it does to surrounding healthy tissue can cause problems with learning and memory, that grow worse over time. It is believed that this decline occurs because the radiation destroys the adult neural stem cells that should be repairing damage. When this happens to a child and you watch them decline mentally at an age when they should be advancing, it can be heart-breaking. That is why I chose to highlight a paper in which injected neural stem cells were able to repair radiation damage in rats and bring back their sensory abilities towards normal. (You can read our blog entry on this research here.)

This month’s literature continued to show progress in using stem cells to reproduce complex tissues made of multiple cell types, something that has always been a touchstone goal for regenerative medicine. One research team was able to grow functional small intestine on a biodegradable scaffold in mice (which we blog about here). Another was able to produce mucus glands with both the inner and outer structures that make up a normal gland (blogged about here).

With heart disease being a leading cause of disability it was good to see advances in heart tissue repair this month from two very different angles. One research team developed a much more efficient way to drive embryonic stem cells to become heart muscle cells, which is the type of cell needed to repair tissue damaged or weakened from a heart attack or congestive heart failure. The other team discovered a compound that can be injected like a drug and that can activate the few adult heart stem cells we all have to be better at repairing tissue (here’s our blog about that work).

I hope you find the somewhat longer descriptions in my full report interesting.

Improved technique for directly converting skin to neurons

This is the way things often go in science: One group announces a breakthrough. Yah! Then for the next several years, scientists all over the world replicate and improve on that breakthrough until it’s finally believable and widely useful.

To people outside science who read about the initial breakthrough, this may look a lot like scientists twiddling their thumbs, sitting on new therapies. But really, do you want a therapy based on a breakthrough that may or may not be real? Right, neither do I.

A paper from Marius Wernig’s lab at Stanford University is a great example of this process. In January, 2010, Wernig’s lab had a paper in Nature announcing their transformation of mouse skin cells directly into neurons. This was exciting work, bringing with it the possibility of directly converting skin from a person with a neuronal disease into neurons that can be studied in the lab. But that work was in mice, and one thing we know from past research is that mice are most certainly not humans.

About a year and a half later, Wernig replicated his work with human cells in another Nature paper, but the transformation was much less efficient than it was with mouse cells (here’s our blog entry on that work). It took weeks for the transformation to take place, only 2 to 4 percent of the skin cells transformed into neurons and those neuronal cells were on the wimpy side. It’s still exciting work — I mean how cool is it that human skin can be turned into neurons with the addition of just four molecules. But ready for therapeutic prime time? I think not.

Now we’ve entered the next stage where scientists all over the world incrementally improve upon the original work until it’s good enough, fast enough and efficient enough to be broadly useful. One such improvement came from the Stanford University lab of Gerald Crabtree, who published his findings in a Nature paper last week.

Crabtree’s lab employed two of the four factors that had been effective for Wernig, but supplemented those with a different kind of molecule — called microRNAs. This change dramatically improved how efficiently the skin cells converted to neurons, and produced neurons with much stronger electrical signaling. Another group from Milan published a paper in early July using three different factors to coerce the transformation from skin to neuron. In their case, the neurons were more like those that are lost in Parkinson’s disease, known as dopaminergic neurons.

A Stanford press release quotes Crabtree:

“It’s been a long time in coming to this,” said Crabtree. “But science often progresses in leaps and starts, and then all of a sudden many scientists come to the same position at the same time. Now these studies have come out, and more will be coming, all of which are going to say that not only can you can make neurons different ways, but also you can make neurons of different types.”

At this point it’s too soon to know which, if any, of these techniques is going to become most widely used. We can probably expect to see more improvements on these approaches coming out of some labs, while other labs start figuring out how this revolutionary transformation can be used to treat or understand disease. Crabtree’s lab, for example, says they are already taking skin cells from people with Down’s syndrome and transforming those into neurons in order to understand the disease and look for therapies.

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CIRM HIV/AIDS disease team technology makes news

Richmond-based Sangamo BioSciences has been making a lot of news lately with their gene editing technology. Theirs is the technique being used in CIRM’S HIV Disease Team Award to John Zaia at The City of Hope (summarized in this San Francisco Business Journal story).

Sangamo’s so-called zinc finger technology can recognize a specific location in the DNA, snip it out, and replace it with a different sequence. In the case of HIV, the molecular zinc scissors are being used to create a mutation in a small region of DNA in blood-forming stem cells.

Those cells altered in the lab lack a working copy of the protein CCR5, which the HIV virus uses to enter and destroy immune cells. The team then plans to transplant those altered stem cells into a person, where they create a new immune system that is resistant to HIV infection. Early results from this work in animals look promising and the team is hoping to be able to enter human clinical trials with the technique in the next few years.

This is one of two CIRM disease teams attempting to generate a stem cell-based therapy for HIV/AIDS. The other award, to Irvin Chen at UCLA, is using a different type of molecule to mutate the CCR5.

Ron Leuty of the San Francisco Business Journal had a story yesterday about Sangamo’s prospects, which include a trial to treat pain associated with diabetes, called diabetic neuropathy. The technique is also being used in research to treat the blood-clotting disease hemophilia B and to create disease-in-a-dish models of heart disease. Reuty wrote about the heart disease work, being carried out by Sangamo and researchers at the Scripps Translational Science Institute:

Using induced pluripotent stem cells — adult stem cells manipulated to give them embryonic-like qualities — researchers will recreate cells that line the arteries. …

“Genome editing allows us to do an experiment no one has ever tried — that is, if you change someone’s genetics, can you make their cells revert away from acquiring a disease?” Samuel Levy, director of genomic sciences at the Scripps Translational Science Institute, said in a press release.

This video describes how the City of Hope team hopes to use the zinc finger technology in their proposed therapy for HIV.

You can also watch talks by City of Hope research John Zaia, CIRM board member and HIV patient advocate Jeff Sheehy, and HIV advocate Loren Leeds when they spoke to the CIRM governing board about the work.

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Stem cells improve brain function after radiation therapy

CIRM grantees at University of California Irvine have used human neural stem cells to help alleviate brain damage that occurs after radiation to treat brain tumors.

Radiation can be an effective way of treating tumors in the brain, but the radiation also kills surrounding healthy tissue in addition to the destroying the tumor. Even if the cancer is eliminated the person can be left with debilitating learning and memory loss. A press release from UCI quotes senior author on the work Charles Limoli, who has a CIRM SEED award to carry out this work:

“In almost every instance, people experience severe cognitive impairment that’s progressive and debilitating,” Limoli said. “Pediatric cancer patients can experience a drop of up to three IQ points per year.”

Limoli and his team wanted to know if the brain’s stem cells could repair that damage. They injected human neural stem cells into the brains of rats that had undergone radiation treatment. Those stem cells migrated to the damaged part of the brain and matured into nerves and the brain’s support cells. The release quotes Limoli:

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years, most likely with patients afflicted with glioblastoma multiforme, a particularly aggressive and deadly form of brain cancer.”

If their work is successful, this technique could help people live normal lives after being treated for brain cancers. That would be good news for individuals, their caregivers and for the state, which loses tax income when people are unable to work or must decrease work to care for family members.

Cancer Research, July 15, 2011
CIRM Funding: Charles Limoli (RS1-00413-1)

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