Posted on Dec 09, 2020, 6 a.m.
Researchers have altered a molecule that is naturally produced in the body to safely guide stem cells to damaged brain tissues. Mice with a fatal brain disease had delayed onset of symptoms and improved survival when given the new molecule and neural stem cells, with further development this approach could have applications for human disease.
Stem cells are part of the body’s repair system. They have the potential to replace specialized cells—such as muscle cells, blood cells, and brain cells—that have been damaged by injury or disease.
The amount of repair that stem cells do in the adult body is limited. Researchers have been looking for ways to draw more stem cells to injured areas and focus their work. Harnessing the body’s healing mechanisms in this way is called regenerative medicine.
To attract stem cells to injured tissues, the body naturally releases chemicals called chemokines. But chemokines also cause inflammation, and long-term inflammation in the brain and body can cause more harm than good. Therefore, it hasn’t been considered safe to use natural chemokines for regenerative medicine.
A research team led by Dr. Evan Snyder from the Sanford Burnham Prebys Medical Discovery Institute tested whether they could engineer a natural chemokine to attract stem cells without causing inflammation. They altered a chemokine called CXCL12, which can draw neural stem cells to sites of injury or disease in the brain and central nervous system. CXCL12 binds to a receptor called CXCR4 on the surface of these stem cells.
When activated, CXCR4 can signal different reactions within the cells. Using computational methods, the researchers optimized the part of CXCL12 that initially binds CXCR4. They then replaced the portion that triggers CXCR4 to boost inflammation. The work was funded in part by NIH’s National Institute of General Medical Sciences (NIGMS). Results were published on November 20, 2020, in Proceedings of the National Academy of Sciences.
After testing different versions of the molecule in laboratory experiments, the team focused on one called SDV1a. SDV1a strongly encouraged neural stem cells to migrate towards its signal without activating genes associated with inflammation. Instead, it activated genes involved in tissue repair.
The team next tested their new molecule in the brains of healthy mice. When they injected SDV1a into one side of the brain and neural stem cells into the other, the cells migrated to the side with SDV1a. Both SDV1a and the stem cells remained active in the brain for weeks. The mice showed no inflammation or other side effects from treatment.
Finally, the researchers gave the combination of SDV1a and neural stem cells to mice with a deadly degenerative brain disorder. SDV1a was injected into the brain’s cortex, and stem cells were implanted into ventricles—brain cavities filled with cerebrospinal fluid.
The stem cells spread throughout the brain and produced new neurons. Mice that received the treatment had slower onset of disease symptoms and lived longer.
“The ability to instruct a stem cell where to go in the body or to a particular region of a given organ is the Holy Grail for regenerative medicine,” Snyder says. “Now, for the first time ever, we can direct a stem cell to a desired location and focus its therapeutic impact.”
The team is now testing their approach in a mouse model of amyotrophic lateral sclerosis (ALS). Similar strategies may help improve stem cell therapy for spinal cord injury and stroke, as well as boost repair in other parts of the body.
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Chemical mutagenesis of a GPCR ligand: Detoxifying "inflammo-attraction" to direct therapeutic stem cell migration. Lee JP, Zhang R, Yan M, Duggineni S, Wakeman DR, Niles WL, Feng Y, Chen J, Hamblin MH, Han EB, Gonzalez R, Fang X, Zhu Y, Wang J, Xu Y, Wenger DA, Seyfried TN, An J, Sidman RL, Huang Z, Snyder EY. Proc Natl Acad Sci U S A. 2020 Nov 20:201911444. doi: 10.1073/pnas.1911444117. Online ahead of print. PMID: 33219123.