In the first hours and days following a stroke, stem cells leave the bone marrow to help the injured brain repair damaged neurons and make new neurons and blood vessels, according to researchers at the Medical College of Georgia.
The research, reported in the May issue of Stroke, used a mouse model in which the animal’s marrow was replaced with that of a transgenic mouse with cells that make a jellyfish protein that fluoresces green so they could trace the cells and the natural repair process that apparently occurs after stroke.
The researchers are now looking for the right factors to enhance the normal repair mechanism, improve stroke recovery and, since the patient’s own cells would be used, avoid issues such as the compatibility of donated stem cells and the ethical controversy surrounding embryonic stem cells.
They also want to identify which bone marrow stem cell types are targeted for this repair and how they are called to the site of injury, suspecting that inflammation may be part of this ‘homing” process.
“We tried to determine whether cells that reside in your bone marrow and circulate throughout the blood could turn into any of the major brain cells types,” said Dr. David Hess, neurologist, stroke specialist, chairman of the MCG Department of Neurology and lead author on the study.
They found in the animal model, evidence that bone marrow cells naturally migrate to injured regions of the brain after stroke to help repair damaged tissue; they also become endothelial cells that form new blood vessels and what appear to be new neurons.
“Such repairs occurred naturally in response to stroke and the bone marrow is involved in those repair mechanisms,” said Dr. William D. Hill, neuroscientist in the MCG Department of Cellular Biology and Anatomy and second author on the research paper. “We think that when you have a stroke, you have this central core area that is highly affected. Then you have this area like a shell surrounding the core, called the penumbra, like a shadow, that has a gradient of damage as you move from the core of the stroke to the unaffected tissue. This is the area that is going to be the most sensitive to being repaired. So maybe if we can enhance that repair, we could preserve a region that would normally die but is an area we can target to recover.”
Enhancement could come through the use of growth factors that affect subsets of bone marrow cells; possibly some already on the market, for example to help leukemia patients rebuild bone marrow after chemotherapy, might be useful.
“If this works out, you will be able to give individuals shots following stroke to boost their bone marrow to proliferate these stem cells to do specific tasks, target specific groups of these stem cells important to blood vessel repair and the genesis of new neurons,” Dr. Hill said. The work has implications for all sorts of brain injuries early and late in life such as cerebral palsy, Parkinson’s and Alzheimer’s disease.
This repair process mimics embryological development when stem cells from the bone marrow help form blood vessels in the brain. “There are some data that older people don’t have as many circulating stem cells as younger, healthier people do,” Dr. Hess said, so enhancing the cell number involved in repair should enhance the natural process.
Enhancing the natural process could avoid more aggressive measures such as transplanting cell-laden bone marrow. “Why would we transplant bone marrow cells into people when their bone marrow already has these cells?” Dr. Hess said. “It makes much more sense to actually maximize what they already put out. Also, rather than taking bone marrow out and injecting it into the brain, why not make use, again, of this natural process that summons the cells to the location of the brain injury?”
Finding what summons the cells to the injury site is key, and the researchers are looking at specific molecules up-regulated in inflammation that they suspect are also involved in homing. “Certain factors released and expressed on the surface of damaged endothelial cells may act as flags to wave down passing white blood cells or stem cells to attach there,” Dr. Hill said.
Also key is identifying which specific stem cells are summoned and are needed to make new blood vessels, support cells and neurons. This may permit selective recruitment and proliferation of just the cells needed for repair, Dr. Hill said.
There are two known broad classes of these cells, hematopoetic and mesenchymal, but there may be many unknown cell types, including a separate group involved in making endothelial cells, Dr. Hess said.
Just last week, through a collaborative study with the Medical University of South Carolina, they received the first mouse that, through a process called clonal analysis, will enable them to tag a single cell, then watch for its descendents’ roles in the normal repair process.
They also are collaborating with fellow MCG researcher Nevin Lambert to do a functional analysis of the new neurons produced by the stem cells to ensure that they not only look like but function as neurons.
The published research was funded by the American Heart Association and has been presented at recent meetings of the association and the Society of Neuroscience. The scientists have received funding from the National Institutes of Health for follow-up studies.