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

Mar. 8, 2013 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 bone loss 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 mesenchymal stem cells, stromal cell-derived factor-1, or SDF-1, turns on a survival pathway called autophagy 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 stem cells' ability to survive and stay in the bone marrow, 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 fat cells 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 food sources, 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.

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