Nav: Home

UCSF researchers control embryonic stem cells with light

August 26, 2015

UC San Francisco researchers have for the first time developed a method to precisely control embryonic stem cell differentiation with beams of light, enabling them to be transformed into neurons in response to a precise external cue.

The technique also revealed an internal timer within stem cells that lets them tune out extraneous biological noise but transform rapidly into mature cells when they detect a consistent, appropriate molecular signal, the authors report in a study published online August 26 in Cell Systems.

"We've discovered a basic mechanism the cell uses to decide whether to pay attention to a developmental cue or to ignore it," said co-senior author Matthew Thomson, PhD, a researcher in the department of Cellular and Molecular Pharmacology and the Center for Systems and Synthetic Biology at UCSF.

During embryonic development, stem cells perform an elaborately timed dance as they transform from their neutral, undifferentiated form to construct all the major organ systems of the body. Researchers have identified many different molecular cues that signal stem cells when to transform into their mature form, whether it be brain or liver or muscle, at just the right time.

These discoveries have raised hopes that taking control of stem cells could let scientists repair damaged and aging tissues using the body's own potential for regeneration. But so far, getting stem cells to follow instructions en masse has proven far more difficult than researchers once expected.

In recent years, scientists have found that many of the genes encoding these developmental cues constantly flip on and off in undifferentiated stem cells. How the cells manage to ignore these noisy fluctuations but then respond quickly and decisively to authentic developmental cues has remained a mystery.

"These cells receive so many varied inputs," said lead author Cameron Sokolik, a Thomson laboratory research assistant at the time of the study. "The question is how does the cell decide when to differentiate?"

To test how stem cells interpret developmental cues as either crucial signals or mere noise, Thomson and colleagues engineered cultured mouse embryonic stem cells in which the researchers could use a pulse of blue light to switch on the Brn2 gene, a potent neural differentiation cue. By adjusting the strength and duration of the light pulses, the researchers could precisely control the Brn2 dosage and watch how the cells respond.

They discovered that if the Brn2 signal was strong enough and long enough, stem cells would quickly begin to transform into neurons. But if the signal was too weak or too brief, the cells ignored it completely.

"The cells are looking at the length of the signal," Thomson said. "That was a big surprise."

To learn how stem cells were able to weed out fleeting Brn2 signals but respond to persistent ones, co-senior author Stanley Qi, PhD, and co-author Yanxia Liu, PhD, both now at Stanford University, used the CRISPR-Cas9 gene editing system to add a fluorescent tag to the transcription factor Nanog, which normally acts as a brake on differentiation. This protein could then be used as a read-out on the cells' decision-making.

The team discovered that Nanog itself is actually key to the cells' impeccable sense of timing. When the Brn2 signal turns on, it disrupts a molecular feedback loop that keeps the cell stable and undifferentiated. In response, Nanog protein levels start to drop. However, the protein takes about four hours to dissipate completely, which makes Nanog an excellent internal stop-watch. If the Brn2 signal is a fluke, Nanog levels can quickly rebound and the cell will do nothing. On the other hand, if Nanog runs out and the Brn2 signal is still on, "it's like a buzzer goes off," Thomson said. "And once it goes, it really goes - the cells rapidly start converting into neurons."

Thomson believes that similar timer mechanisms may govern stem cell differentiation into many different tissues.

"It's hard for a cell to be both tolerant and fast, to reject minor fluctuations, but respond very precisely and sharply when it sees a signal," he said. "This mechanism is able to do that."

Thomson is a UCSF Sandler Fellow and Systems Biology Fellow. Since 1998, these unique fellowship programs have enabled UCSF to recruit young researchers straight out of graduate school to pursue ambitious high-risk, high-reward science.

Thomson's ambitious big idea is to use the light-inducible differentiation technology his group has developed to study how stem cells produce complex tissues in three dimensions. He imagines a day when researchers can illuminate a bath of undifferentiated stem cells with a pattern of different colors of light and come back the next day to find a complex pattern of blood and nerve and liver tissue forming an organ that can be transplanted into a patient.

"There's lots of promise that we can do these miraculous things like tissue repair or even growing new organs, but in practice, manipulating stem cells has been notoriously noisy, inefficient, and difficult to control," Thomson said. "I think it's because the cell is not a puppet. It's an agent that is constantly interpreting information, like a brain. If we want to precisely manipulate cell fate, we have to understand the information-processing mechanisms in the cell that control how it responds to the things we're trying to do to it."
-end-
David A. Sivak, PhD, now at Simon Fraser University, was also a senior author on the study. Additional co-authors were David Bauer, PhD, Jade McPherson, PhD, Michael Broeker, PhD, and Graham Heimberg, PhD, all at UCSF.

Funders of the work include the UCSF Center for Systems and Synthetic Biology, the National Institute of General Medical Sciences, the NIH Office of the Director, the National Cancer Institute, and the National Institute of Dental & Craniofacial Research (NIGMS P50 GM081879, NIH DP5 OD012194 and NIH DP5 OD017887).

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospital San Francisco.

University of California - San Francisco

Related Stem Cells Articles:

A protein that stem cells require could be a target in killing breast cancer cells
Researchers have identified a protein that must be present in order for mammary stem cells to perform their normal functions.
Approaching a decades-old goal: Making blood stem cells from patients' own cells
Researchers at Boston Children's Hospital have, for the first time, generated blood-forming stem cells in the lab using pluripotent stem cells, which can make virtually every cell type in the body.
New research finds novel method for generating airway cells from stem cells
Researchers have developed a new approach for growing and studying cells they hope one day will lead to curing lung diseases such as cystic fibrosis through 'personalized medicine.'
Mature heart muscle cells created in the laboratory from stem cells
Generating mature and viable heart muscle cells from human or other animal stem cells has proven difficult for biologists.
Mutations in bone cells can drive leukemia in neighboring stem cells
DNA mutations in bone cells that support blood development can drive leukemia formation in nearby blood stem cells.
Scientists take aging cardiac stem cells out of semiretirement to improve stem cell therapy
With age, the chromosomes of our cardiac stem cells compress as they move into a state of safe, semiretirement.
Purest yet liver-like cells generated from induced pluripotent stem cells
A team of researchers from the Medical University of South Carolina and elsewhere has found a better way to purify liver cells made from induced pluripotent stem cells.
Stem cell scientists discover genetic switch to increase supply of stem cells from cord blood
International stem cell scientists, co-led in Canada by Dr. John Dick and in the Netherlands by Dr.
Stem cells from diabetic patients coaxed to become insulin-secreting cells
Signaling a potential new approach to treating diabetes, researchers at Washington University School of Medicine in St.

Related Stem Cells Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Setbacks
Failure can feel lonely and final. But can we learn from failure, even reframe it, to feel more like a temporary setback? This hour, TED speakers on changing a crushing defeat into a stepping stone. Guests include entrepreneur Leticia Gasca, psychology professor Alison Ledgerwood, astronomer Phil Plait, former professional athlete Charly Haversat, and UPS training manager Jon Bowers.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".