Signaling molecule may help stem cells focus on making bone despite age, disease

March 8, 2013
Samuel Herberg (from left) and Drs. William Hill and Carlos Isales. Credit: Tim Conway

A signaling molecule that helps stem cells survive in the naturally low-oxygen environment inside the bone marrow may hold clues to helping the cells survive when the going gets worse with age and disease, researchers report.

They hope the findings, reported in PLOS ONE, will result in better therapies to prevent in aging and enhance success of stem cell transplants for a wide variety of conditions from heart disease to cerebral palsy and cancer.

They've found that inside the usual, oxygen-poor niche of , stromal cell-derived factor-1, or SDF-1, turns on a survival pathway called that helps the cells stay in place and focused on making bone, said Dr. William D. Hill, stem cell researcher at the Medical College of Georgia at Georgia Regents University and the study's corresponding author.

Unfortunately with age or disease, SDF-1 appears to change its tune, instead reducing ' ability to survive and stay in the , said Samuel Herberg, GRU graduate student and the study's first author. Additionally cells that do stay put may be less likely to make bone and more likely to turn into in the marrow.

The researchers believe it's the changes in the normal environment that come with age or illness, including diminished nutrition, that prompt SDF-1's shifting role.

"You put new cells in there and, all of the sudden, you put them in a neighborhood where they are being attacked," Hill said. "If we can somehow precondition the transplanted cells or modify the environment they are going into so they have higher levels of autophagy, they will survive that stress."

Autophagy is the consummate green, survival pathway, where the cell perpetuates itself by essentially eating itself over and over again, in the face of low , other stress or needing to eliminate damaged or toxic product buildup. The researchers believe autophagy slows with age, so deadly trash starts piling up in and around cells, Hill said.

"Your cells normally have a reminder to take out the trash," said Dr. Carlos Isales, MCG endocrinologist and Clinical Director of the GRU Institute of Regenerative and Reparative Medicine. "That reminder, SDF-1, becomes inconsistent as you get older, so rather than being an activator of the trash signal, it becomes an inhibitor."

Herberg led efforts to genetically modify stem cells from mice to overexpress SDF-1 – in fact the researchers were in the enviable position of being able to adjust expression up or down – and control autophagy in their novel cells. They found that while SDF-1 didn't increase stem cell numbers, it protected stem cells hazards related to low oxygen and more by increasing autophagy while decreasing its antithesis, programmed cell death, or apoptosis.

"They get away with lower oxygen needs and lower nutrient needs and stem cells are able to survive in a hostile environment as they are attacked by damaging molecules like free radicals," Hill said. In fact, the cells can thrive.

"The success of is mixed and we think part of the problem is the environment the cells are put into," said Isales. "Ultimately we want to find out what is the triggering event for aging, what is the chicken, what is the egg and what initiates this cascade. This new finding gives us a piece of the puzzle that helps us see the big picture."

They've already begun looking at what happens to SDF-1 in human bone marrow stem cells and have identified a couple of drugs used to treat other conditions that increase SDF-1 production and protection. They envision a collagen matrix, almost like a raft, that delivers SDF-1 and stem cells or SDF-1 alone where needed, enabling targeted bone regrowth in the case of a bad fracture, for example.

It was already known that stem cells secrete SDF-1 and that the cell survival pathway, autophagy, was up-regulated in stem cells. "We started thinking, if SDF-1 is secreted here in response to low oxygen, it must be important in cell survival," said Hill and the researchers became the first to put the pieces together.

Cell survival and its antithesis, apoptosis, are both tightly regulated and necessary, Herberg notes. And, in excess, both can be deadly. In fact, cancer therapies are under study that block autophagy with the idea of making cancer more vulnerable to chemotherapy. One of SDF-1's major roles is helping the body properly assemble during development. It's produced by stem cells and found in high levels in the lungs and bones. MCG researchers are looking for other sources of SDF-1 production in the body and how those might change with age.

Bone formation tends to decrease at about age 60, notes Isales, principal investigator on the $6.3 million Program Project Grant from the National Institutes of Health that funded the study.

Explore further: Researchers work to turn back the clock on bone-producing stem cells

Related Stories

Researchers work to turn back the clock on bone-producing stem cells

June 9, 2011
Researchers want to turn back the clock on aging stem cells so they'll make better bone.

Stem cell survival strategy key to blood and immune system health

February 14, 2013
Stem cells of the aging bone marrow recycle their own molecules to survive and keep replenishing the blood and immune systems as the body ages, researchers at UC San Francisco (UCSF) have discovered.

Stem cell 'homing' signal may help treat heart failure patients

February 21, 2013
In the first human study of its kind, researchers activated heart failure patients' stem cells with gene therapy to improve their symptoms, heart function and quality of life, according to a study in the American Heart Association ...

Recommended for you

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

New animal models for hepatitis C could pave the way for a vaccine

July 19, 2017
They say that an ounce of prevention is worth a pound of cure. In the case of hepatitis C—a disease that affects nearly 71 million people worldwide, causing cirrhosis and liver cancer if left untreated—it might be worth ...

Omega-3 fatty acids fight inflammation via cannabinoids

July 18, 2017
Chemical compounds called cannabinoids are found in marijuana and also are produced naturally in the body from omega-3 fatty acids. A well-known cannabinoid in marijuana, tetrahydrocannabinol, is responsible for some of its ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.