Unlike conventional bone marrow transplants that focus on hematopoietic stem cells, which produce red and white blood cells, transplants of mesenchymal stem cells, which can produce bone-building cells, don’t fare well, said Dr. David Hill, a research physiologist at GRU and Charlie Norwood VA Medical Center.
He and a group of researchers at GRU were looking at a cell signal called stromal derived factor-1, or SDF-1, that seems to be important in stem cell survival.
Doctoral student Samuel Herberg looked at cells that had been genetically engineered to put out 30 times as much of SDF-1 as normal and found increased survival after transplant. He suspected it might be from either decreasing apoptosis, or cell death, or increasing autophagy, the cell’s ability under stress to recycle its own cell products for nutrients for survival.
It turned out to be both because the two are in a fine balance, he said.
“This balance is extremely important, and that is why we attempted to look at both at the same time,” Herberg said. “What we found is that balance is tipping over to autophagy by decreasing apoptosis.”
Helping to increase what is both a survival mechanism and a maintenance mechanism is important, said Dr. Carlos Isales, the clinical director of the GRU Institute of Regenerative and Reparative Medicine.
“Some people have compared this process, the autophagy, to taking out the garbage, the way the cell takes out the garbage,” he said. “Part of the aging process is the cells forget to take out the garbage, this autophagy is impaired. The question is: Do people age because cells forget to take out the garbage?”
The researchers are now looking at whether SDF-1 can affect that process, Hill said, at “how can we upregulate autophagy during aging so these cells are healthy and function properly as well as survive, as opposed to dying off with age.”
The research group plans to compare bone marrow from older and younger orthopedic patients to see whether there is a difference that can be affected. The group is also looking at a potential drug treatment with a provisional patent that could increase SDF-1, either in stem cells before they are transplanted or after the fact, that would also include affecting the cells already there, Hill said.
Part of the problem is overcoming the hostile environment those cells will face, which might be why stem cell transplantation thus far has not had the success envisioned for it, Isales said.
“I know in talking with the FDA (Food and Drug Administration) they’ve been very disappointed in a lot of the regenerative medicine approaches involving stem cell transplantation because it looks like it’s minor improvements over existing therapies,” Hill said. “We’re really looking at ways we can change that. We can create something that is a large enough difference that it’s worth using this approach as opposed to a more standard therapeutic approach.”
The group has a $6.3 million Program Project grant from the National Institutes of Health and has filed for a supplement to work on more approaches that would translate to the clinic, Isales said.
They hope to create something through transplanting the mesenchymal stem cells or other stem cells that could treat acute injury, such as fracture, Hill said.
“We’re actively pursuing those projects right now,” he said. “It’s not there yet but that is one of the things we are shooting for.”