Study Finds Effective Approach for Delivering Stem Cells to Repair Stroke Damage

A new Miller School research study has identified a safe and effective route for delivering stem cells to the brain, where they can potentially repair stroke-damaged tissue.

“Our team found that delivering a low dose of mesenchymal stem cells (MSCs) through the carotid artery at 24 hours after stroke resulted in effective therapy for ischemic stroke in an animal model,” said lead author Dileep Yavagal, M.D., associate professor of clinical neurology and neurological surgery, Director of Interventional Neurology, and Co-Director of Endovascular Neurosurgery. It is the first study to identify a safe dose for intra-arterial delivery of MSCs in a rat stroke model and show the dose to be effective.

“There continues to be a critical need for novel therapies for stroke,” Yavagal added. “Now that we have a scientific foundation in place, we can begin to design clinical trials to translate these laboratory results into treatment strategies.” MSCs in this study were harvested from bone marrow of healthy animals.

The Miller School study, “Efficacy and Dose-Dependent Safety of Intra-Arterial Delivery of Mesenchymal Stem Cells in a Rodent Stroke Model,” was published this week in PLOS ONE, an international research journal.

Stroke is one of the nation’s leading causes of death and long-term disability, with an estimated annual cost of $73.3 billion in 2010. Medical researchers have known for more than a decade that MSCs – derived from bone marrow, adipose (fatty) tissue or other sources – can help repair stroke-damaged brain tissue. However, the most effective delivery method for stem cells for stroke has been unclear.

Implanting the stem cells directly into the stroke-affected region of the brain involves an invasive surgical procedure, a higher-risk approach that has not gone beyond two early clinical trials, said Yavagal. A less invasive approach involves injecting the stem cells into a vein; however, more than 95 percent of the stem cells delivered via vein wind up trapped in the lungs and liver, and only a small percentage reach the brain.

In contrast, injecting MSCs into the carotid artery on the side of the stroke through a tiny catheter is a minimally invasive procedure that enables the stem cells to go directly to the stroke-injured area in the brain in large numbers. One of the major hurdles in the past for this approach has been the large size of many MSCs, ranging from 5 to 50 microns, which can block tiny capillaries and decrease blood flow to the brain. As a result, delivering a large dose of MSCs at one time can have an adverse effect in animal models. The new study by Yavagal, under the mentorship of Joshua M. Hare, M.D., Director of the Interdisciplinary Stem Cell Institute, has overcome this major hurdle for translating this potential therapy to the clinic.

“The key is to find a treatment strategy that delivers enough of the stem cells to be effective in repairing tissue without compromising the blood flow,” said Yavagal. “In our study, we found that substantially reducing the dose of stem cells and delivering at 24 hours after the stroke in the animal model resulted in a safe (no compromise of blood flow) and effective solution,” said Yavagal. “Now that we have a better understanding of the right balance, we can consider how to take the next step forward, in keeping with our growing focus on regenerative medicine in helping patients with stroke.”

Miller School coauthors were Ami P. Raval, Ph.D., research assistant professor of neurology; Chuanhui Dong, Ph.D., research assistant professor of neurology; Weizhao Zhao, Ph.D., associate professor of neurology; Tatjana Rundek, M.D., Ph.D., professor of neurology; Ralph L. Sacco, M.D., M.S., professor and Olemberg Chair of Neurology; and Miguel Perez-Pinzon, Ph.D., professor of neurology and Director of the Cerebral Vascular Disease Research Center.

Yavagal led the first intra-arterial stem cell trial in the U.S., RECOVER-Stroke. An active member of the Miller School’s Interdisciplinary Stem Cell Institute research team, Yavagal is a peer reviewer for several journals including Stroke, Neurology, Journal for Neurointerventional Surgery and the Journal of Neuroimaging, and has given presentations both nationally and internationally on topics related to neuroscience and neurointervention.

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