If the blood vessels of the brain become plugged as a result of a clot or some other obstructive event, then the brain suffers a trans-ischemic attack (TIA), which is more commonly known as a stroke. The initial stroke starves brain cells of oxygen, which causes cell death by suffocation. However, dying brain cells often spill enormous amounts of lethal material into the surrounding area, which kills off even more brain cells. Worse still, these dead or dying called can induce inflammation in the brain, which continues to kill off brain cells.
New work, however, from the laboratory of César Borlongan at the University of Southern Florida in Tampa, indicates that the spleen may be a target for treating the stroke-induced chronic inflammation that continues to kill brain cells after the initial stroke.
At the University of Florida Center of Excellence for Aging and Brain Repair, a study found that the intravenous administration of human bone marrow stem cells to post-stroke rats reduced the inflammatory-plagued secondary cell death associated with stroke progression in the brain. The intravenously administered cells preferentially migrated to the spleen where they reduced this post-stroke inflammation.
This study answers some of the perplexing questions surrounding animal experiments that used stem cells to treat stroke. Typically, stem cell administration to animals that suffered an artificially-induced stroke causes some functional recovery, but when their brains are examined for the stem cells that were implanted into them, very few surviving cells are observed.
“Our findings suggest that even if stem cells do not enter the brain or survive there, as long as the transplanted cells survive in the spleen the anti-inflammatory effect they promote may be sufficient enough to therapeutically benefit the stroke brain,” said César Borlongan, principal investigator of this study.
Stroke is the leading cause of death and the number one cause of chronic disability in the United States, yet treatment options are limited.
Stem cell therapy has emerged as a potential treatment for ischemic stroke, but most pre-clinical studies have examined the effects of stem cells transplanted during acute stroke (one hour to three hours aster the onset of the stroke).
In the wake of an acute stroke, an initial brain lesion forms from the lack of blood flow to the brain. The blood-brain barrier is also breached and this allows the infiltration of inflammatory molecules that trigger secondary brain cell death in the weeks and months that follow. This expanded inflammation is the hallmark of chronic stroke.
In this study, Borlongan and his colleagues intravenously administered human bone marrow stem cells 60 days after the onset of a stroke. Thus these animals were well into the chronic stroke stage.
The transplanted stem cells predominantly homes to the spleen. In fact, Borlongan and his crew found 30-times more cells in the spleens of the animals than in the brain.
While in the spleen, the stem cells squelched the production of a protein called tumor necrosis factor, which is a major inflammatory signal that increases in concentration after a stroke. The reduction of the tumor necrosis factor signal prevented the macrophages and other immune cells from leaving the spleen and going to the brain. This reduced systemic inflammation and decreased the size of the lesions in the brain caused by the stroke. There was also a trend toward reduced neuronal death and smaller decreases in learning and memory in the laboratory animals.
Borlongan explained that during the chronic stage of stroke, macrophages seem to fuel inflammation. “If we can find a way to effectively block the fuel with stem cells, then we may prevent the spread of damage in the brain and ameliorate the disabling symptoms many stroke patients live with,” said Borlongan.
Borlongan and his team hope to test whether transplanting human bone marrow stem cells directly into the spleen will lead to behavioral recovery in post-stroke rats.
One drug that has been approved for the emergency treatment of stroke is tPA or tissue plasminogen activating factor, which activates the blood-based protein plasminogen to form the highly active enzyme, plasmin. Plasmin is a powerful dissolved of clots, but tPA must be administered less than 4.5 hours after the onset of ischemic stroke, and benefits only three to four percent of patients.
Even though more work needs to be done, evidence from the USF group and other neurobiology groups indicates that stem fells may provide a more effective treatment for stroke over a wider time frame.
Targeting the spleen with stem cells or the anti-inflammatory molecules they sec rate offers hope for treating chronic neurodegenerative diseases like stroke at later stages.
This study, which was published in the journal Stroke, shows that it is possible to arrest the chronic inflammation that characterizes chronic stroke 60 days after the initial stroke. If such a result can be replicated in human patients, it will indeed be a powerful thing, according the Sandra Acosta, the first author on this paper.