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

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.

"The success of stem cell transplants 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.