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Exosome Injection Reportedly Enhances Stroke Recovery in Rats

Collins, Thomas R.

doi: 10.1097/01.NT.0000438148.22688.b9
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Investigators reported that exosomes reportedly enhanced neurological function, promoted neurite remodeling, and increased synaptic plasticity and angiogenesis in rats in which stroke had been induced.

Administering exosomes derived from multipotent mesenchymal stromal cells (MSCs) enhanced stroke recovery in rats and might present a treatment alternative to using the cells themselves, researchers reported in a paper published online Aug. 21 in the Journal of Cerebral Blood Flow & Metabolism.

The exosomes reportedly enhanced neurological function, promoted neurite remodeling, and increased synaptic plasticity and angiogenesis in rats in which stroke had been induced. These improvements were seen at significant levels compared to rats treated only with a saline solution.

There has been an increased interest in the clinical applications of exosomes, as researchers learn more about the role they can play in coagulation, intercellular signaling, and waste management. Exosomes — vesicles or tiny lipid containers, which are produced by a wide variety of cells — are only 40 to 100 nm in diameter. They are either released from the cell when multivesicular bodies fuse with the plasma membrane or they are released directly from the plasma membrane. Scientists have hypothesized that because exosomes can merge with and release their contents into cells that are distant from their cell of origin, they may influence processes in the recipient cell.

“We found that essentially exosomes do the same things that the stem cells do,” said Michael Chopp, PhD, professor and vice chair of the department of neurology at Henry Ford Hospital in Detroit. “These exosomes mediate brain plasticity and promote neurologic recovery after stroke. This has extremely wide potential implications to the treatment of many diseases.”

“Exosomes may work because they contain microRNAs, which act as “master switches” for gene translation, setting into motion a “symphony of recovery,” Dr. Chopp said.

The study was a proof of concept, Dr. Chopp stressed, but what has his research team so intrigued is that the findings open the possibility of a treatment that might bring all the benefits of actual cell delivery without the known risks. With full cell delivery comes the possibility of microvessels being occluded, tumors generated, as well as immunologic effects. With the exosomes alone, those potential harms might be avoided, Dr. Chopp said.

“Quite clearly much more work has to be done, but at least we haven't found any adverse effects,” he said.

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In this study, rats had strokes induced by middle cerebral artery occlusion; 24 hours later, either 100 μg protein of MSC-generated exosomes in 0.5 mL of saline, or a placebo of 0.5 mL of saline alone, was injected into the tail vein.

Researchers found a variety of benefits in the exosome group not seen in the placebo group. Starting two days after treatment, those getting the exosomes performed significantly better on two measures of function — the foot-fault test, which measures how accurately a rat can step across a horizontal ladder, and the modified neurological severity score, which measures motor, sensory, reflex and balance abilities (p<.05).

They found that axonal density in the ischemic boundary zone was significantly increased by exosome treatment compared to controls (p<.05).

They also looked at the presence of synaptophysin, a pre-synaptic vesicle protein that indicates synaptic plasticity and synaptogenesis, and found that it was significantly increased in the exosome group compared to controls (p<.05).

Doublecortin, a protein expressed by migrating neuroblasts and a sign of neurogenesis, was measured as well, and the percentage of doublecortin-positive cells was greater in the ischemic boundary zone of the exosome group than the controls (p<.05).

An encouraging fact about the seeming effectiveness of exosomes in stroke recovery is that they are so readily produced, Dr. Chopp said.

“We found that stem cells essentially act as factories for the production of exosomes,” he said. “So you could simply go into the kitchen and produce as many exosomes as you want and then you could play around with different dosing, different intervals of dosing, therapeutic windows.”

Dr. Chopp cautioned that the study isn't final proof of the superiority of exosomes. “We have to optimize it,” he said. “It may be superior to using stem cells, it may not be.”

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Sean Savitz, MD, professor of neurology at the University of Texas Medical School at Houston, who is researching stem cell therapy for stroke, cautioned that, while the findings are a good starting point, there are myriad questions remaining to be answered about the therapeutic use of exosomes.

“It remains to be seen what the full effects are here,” he said. “It's such a hot area right now... we're only beginning to see the first studies that are coming out on exosomes themselves as a therapeutic approach for a range of different disorders. So I think that it will come up in subsequent studies to determine the full effects.

“The smaller size of exosomes might mean that they go to different places than full cells — their destination or destinations simply aren't known.

“They didn't actually label these pieces and determine the biodistribution of where the exosomes went — that's a big question,” Dr. Savitz said. “If they're small they may go in other places and whether that's a good thing or a bad thing has to be determined.”

Whether an intact cell is actually needed to perform some of the functions they've been found to perform — for instance, modulating the immune system — is another open question. “Can that be replicated using just exosomes? We don't know yet,” he said.



A controversy surrounding stem cells is whether they enter the brain — and the small size of exosomes boosts the possibility that they enter the brain, so that is something that will need to be answered.

Then there is the matter of the manufacturing of exosomes and their reproducibility — which hasn't even been fully optimized for full cells yet, he said.

“What's the homogeneity versus heterogeneity of exosomes? That's probably going to depend on a number of variables,” he said. “That's going to depend upon the culture conditions the cells were initially brought up in and the media that was used may, as well, be an important variable to consider in addition to the actual process of generating exosomes.”

In the end, direct comparisons of exosomes and full cells will have to be shown. “It would be really helpful to have that comparison,” he said. “I don't think this approach will replace active cell therapy platforms at this time but there sure is a lot of promise and potential in this work.”

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•. Xin H, Li Y, Cui Y, et al. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 2013; E-pub 2013 Aug 21.
    •. Neurology Today archive on exome sequencing:
      © 2013 American Academy of Neurology