Stem Cell Stories that Caught our Eye: Skin Cells to Brain Cells in One Fell Swoop, #WeAreResearch Goes Viral, and Genes Helps Stem Cells Fight Disease

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Building a Better Brain Cell. Thanks to advances in stem cell biology, scientists have found ways to turn adult cells, such as skin cells, back into cells that closely resemble embryonic stem cells. They can then coax them into becoming virtually any cell in the body.

But scientists have more recently begun to devise ways to change cells from one type into another without first having to go back to a stem cell-like state. And now, a team from Washington University in St. Louis has done exactly that.

As reported this week in New Scientist, researcher Andrew Yoo and his team used microRNAs—a type of ‘signaling molecule’—to reprogram adult human skin cells into medium spiny neurons(MSNs), the type of brain cell involved in the deadly neurodegenerative condition, Huntington’s disease.

“Within four weeks the skin cells had changed into MSNs. When put into the brains of mice, the cells survived for at least six months and made connections with the native tissue,” explained New Scientist’s Clare Wilson.

This process, called ‘transdifferentiation,’ has the potential to serve as a faster, potentially safer alternative to creating stem cells.

#WeAreResearch Puts a Face on Science. The latest research breakthroughs often focus on the science itself, and deservedly so. But exactly who performed that research, the close-knit team who spent many hours at the lab bench and together worked to solve a key scientific problem, can sometimes get lost in the shuffle.

#WeAreResearch submission from The Thomson Lab at the University of California, San Francisco. This lab uses optogenetics, and RNAseq to probe cell fate decisions.

#WeAreResearch submission from The Thomson Lab at the University of California, San Francisco. This lab uses optogenetics, and RNAseq to probe cell fate decisions.

Enter #WeAreResearch, a new campaign led by the American Society for Cell Biology (ASCB) that seeks to show off science’s more ‘human side.’

Many California-based stem cell teams have participated—including CIRM grantee Larry Goldstein and his lab!

Check out the entire collection of submissions and, if you’re a member of a lab, submit your own. Prizes await the best submissions—so now’s your chance to get creative.

New Genes Help Stem Cells Fight Infection. Finally, UCLA scientists have discovered how stem cells ‘team up’ with a newly discovered set of genes in order to stave off infection.

Reporting in the latest issue of the journal Current Biology, and summarized in a UCLA news release, Julian Martinez-Agosto and his team describe how two genes—adorably named Yorkie and Scalloped—set in motion a series of events, a molecular Rube Goldberg device, that transforms stem cells into a type of immune system cell.

Importantly, the team found that without these genes, the wrong kind of cell gets made—meaning that these genes play a central role in the body’s healthy immune response.

Mapping out the complex signaling patterns that exist between genes and cells is crucial as researchers try and find ways to, in this case, improve the body’s immune response by manipulating them.

Harder, Better, Faster, Stronger: Scientists Work to Create Improved Immune System One Cell at a Time

The human immune system is the body’s best defense against invaders. But even our hardy immune systems can sometimes be outpaced by particularly dangerous bacteria, viruses or other pathogens, or even by cancer.

Salk Institute scientists have developed a new cellular reprogramming technique that could one day boost a weakened immune system.

Salk Institute scientists have developed a new cellular reprogramming technique that could one day boost a weakened immune system.

But what if we could give our immune system a boost when it needs it most? Last week scientists at the Salk Institute for Biological Sciences devised a new method of doing just that.

Reporting in the latest issue of the journal Stem Cells, Dr. Juan Carlos Izpisua Belmonte and his team announce a new method of creating—and then transplanting—white blood cells into laboratory mice. This new and improved method could have significant ramifications for how doctors attack the most relentless disease.

The authors achieved this transformation through the reprogramming of skin cells into white blood cells. This process builds on induced pluripotent stem cell, or iPS cell, technology, in which the introduction of a set of genes can effectively turn one cell type into another.

This Nobel prize-winning approach, while revolutionary, is still a many months’ long process. In this study, the Salk team found a way to shorten the cellular ‘reprogramming’ process from several months to just a few weeks.

“The process is quick and safe in mice,” said Izpisua Belmonte in a news release. “It circumvents long-standing obstacles that have plagued the reprogramming of human cells for therapeutic and regenerative purposes.”

Traditional reprogramming methods change one cell type, such as a skin cell, into a different cell type by first taking them back into a stem cell-like, or ‘pluripotent’ state. But here, the research team didn’t take the cells all the way back to pluripotency. Instead, they simply wiped the cell’s memory—and gave it a new one. As first author Dr. Ignacio Sancho-Martinez explained:

“We tell skin cells to forget what they are and become what we tell them to be—in this case, white blood cells. Only two biological molecules are needed to induce such cellular memory loss and to direct a new cell fate.”

This technique, which they dubbed ‘indirect lineage conversion,’ uses the molecule SOX2 to wipe the skin cell’s memory. They then use another molecule called miRNA 125b to reprogram the cell into a white blood cell.

These newly generated cells appear to engraft far better than cells derived from traditional iPS cell technology, opening the door to therapies that more effectively introduce these immune cells into the human body. As Sanchi-Martinez so eloquently stated:

“It is fair to say that the promise of stem cell transplantation is now closer to realization.”

Creaky Cell Machinery Affects the Aging Immune System, CIRM-Funded Study Finds

Why do our immune systems weaken over time? Why are people over the age of 60 more susceptible to life-threatening infections and many forms of cancer? There’s no one answer to these questions—but scientists at the University of California, San Francisco (UCSF), have uncovered an important mechanism behind this phenomenon.

Reporting in the latest issue of the journal Nature, UCSF’s Dr. Emmanuelle Passegué and her team describe how blood and immune cells must be continually replenished over the lifetime of an organism. As that organism ages the complex cellular machinery that churns out new cells begins to falter. And when that happens, the body can become more susceptible to deadly infections, such as pneumonia.

As Passegué so definitively put it in a UCSF news release:

“We have found the cellular mechanism responsible for the inability of blood-forming cells to maintain blood production over time in an old organism, and have identified molecular defects that could be restored for rejuvenation therapies.”

The research team, which examined this mechanism in old mice, focused their efforts on hematopoetic stem cells—a type of stem cell that is responsible for producing new blood and immune cells. These stem cells are present throughout an organism’s lifetime, regularly dividing to preserve their own numbers.

Molecular tags of DNA damage are highlighted in green in blood-forming stem cells. [Credit: UCSF]

Molecular tags of DNA damage are highlighted in green in blood-forming stem cells. [Credit: UCSF]

But in an aging organism, these cells’ ability to generate new copies is not as good as it used to be. When the research team dug deeper they found a key bit of cellular machinery, called the mini-chromosome maintenance helicase, breaks down. When that happens, the DNA inside the cell can’t replicate itself properly—and the newly generated cell is not running on all cylinders.

One of the first things that these old stem cells lose as a result is their ability to make B cells. B cells, a key component of the immune system, normally make antibodies that fight infection. As B cell numbers dwindle in an aging organism, so too does their ability to fight infection. As a result the organism’s risk for contracting dangerous illnesses skyrockets.

This research, which was funded in part by CIRM, not only informs what goes wrong in an aging organism at the molecular level, but also points to new targets that could keep these stem cells functioning at full capacity, helping promote so-called ‘healthy aging.’ As Passegué added:

“Everybody talks about healthier aging. The decline of stem-cell function is a big part of age-related problems. Achieving longer lives relies in part on achieving a better understanding of why stem cells are not able to maintain optimal functioning.”

Out with the Old and in with the New: Starvation Sparks Stem Cells to Replenish Immune System

New research from California scientists has revealed a startling side effect to prolonged starvation, or fasting.

In the latest issue of the journal Cell Stem Cell, scientists from the University of Southern California describe how fasting triggers the human immune system to flush out old, damaged cells and replace them with new ones. This marks the first time that this phenomenon has been directly observed, and has major implications for diseases associated with a declining immune system, including a variety of age-related conditions and cancer chemotherapy.

Scientists have discovered how cycles of prolonged fasting can help flush out damaged immune system cells.

Scientists have discovered how cycles of prolonged fasting can help flush out damaged immune system cells.

In lab experiments first in animal models, and then followed by a Phase 1 human clinical trial, the research team found that regular cycles of fasting, each lasting two to four days, triggered the immune system to flush out immune cells. Much to the team’s surprise, however, they also found that these fasting cycles also triggered stem cells—which had been dormant—to spring into action and produce a fresh supply.

While initially unexpected, these findings made sense to the team. As corresponding author Dr. Valter Longo explained in today’s news release:

“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged. What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back. So we started thinking, well, where does it come from?”

Scientists have long known that when fasting, your body turns to its reserves for nutrients, using up stores of glucose and fat. At the same time, your body also breaks down white blood cells—the major component of the immune system.

So, Longo and his team mapped precisely how this change takes place. They observed that prolonged fasting also reduced levels of an enzyme called PKA. In a previous study, the team had found a link between reduced PKA levels and increased longevity in simple organisms. Research by other groups also found a connection between PKA and the ability of stem cells to self-renew. In this study, the team further defined that relationship. As Longo continued:

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. And the good news is that the body got rid of the parts of the system that might be damaged or old…during fasting. Now if you start with a system heavily damaged, fasting cycles can generate, literally, a new immune system.”

These findings are particularly encouraging with regards to chemotherapy, which has the unfortunate side effect of often damaging the body’s immune system. But if the patient also participates in cycles of fasting, Longo and his team hypothesize that this could help repair their immune system at a much faster pace, improving their quality of life during treatment.

In order to test this hypothesis, the team then turned to the Phase 1 human clinical trial. They instructed patients currently undergoing chemotherapy to fast for a period of 72 hours. The team found that this fasting did protect against at least some of the toxic effects of chemotherapy treatment.

The next steps, says Longo, are to conduct additional experiments in both animal models and clinical trials. But the team is optimistic that these results could apply beyond chemotherapy.

“We are investigating the possibility that these effects are applicable to many different systems and organs, not just the immune system.”