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Signal that helps stem cells make bone despite age or disease
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.
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.
Scientists' have 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,
according to Dr. William D. Hill, of the Medical College
of Georgia, at Georgia Regents University.
Unfortunately with age or disease, SDF-1 reduces stem cells' ability to survive and stay in the bone marrow, adds Samuel Herberg, GRU graduate student and the study's first author. Cells that do stay put may become less likely to make bone and more likely to create 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" pathway, where a cell
essentially eats itself over and over again, due to stress,
lack of nourishment, or needing to eliminate damage or
toxic buildup.
The researchers believe autophagy slows with advancing age,
and deadly 'trash' piles up in and around cells, says Hill.
"Your cells normally have a reminder to take out the trash.
That reminder, SDF-1, becomes inconsistent as you get older,
so rather than being an activator of the trash signal,
it becomes an inhibitor."
Dr. Carlos Isales
MCG endocrinologist, Clinical Director
GRU Institute of Regenerative
and Reparative Medicine
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 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.
In excess, both can be deadly. 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
in the body and what changes might arise 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.
Original article: http://www.eurekalert.org/pub_releases/2013-03/mcog-smm030813.php
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