Cell Transplantation The Regenerative Medicine Journal
Breaching the BBB with mannitol to treat stroke with stem cell therapy means patients can safely and efficiently receive multiple, low dose stem cell treatments
Putnam Valley, NY. (May 26, 2016) – The blood brain barrier (BBB) that separates circulating blood from the brain’s extracellular fluid (BECF) in the central nervous system (CNS) has been called “highly selective” because it selectively and protectively allows permeability. While stem cell therapy has emerged as a treatment possibility for stroke, researchers have been challenged by how to get stem cells past the BBB and into the CNS where in the chronic stages of stroke they can potentially be therapeutic.
Now, researchers at the University of South Florida are carrying out studies using animals modeled with stroke have found that mannitol, a sugar found in a wide variety of natural products, including almost all plants, can safely and efficiently help breach the BBB and facilitate the transport of stem cells into the CNS to treat stroke. A known BBB permeabilizer, mannitol, has been used for several medicinal purposes, including in eye drops to treat glaucoma and to reduce brain swelling after stroke. The authors of the current study have previously shown that mannitol can increase the effectiveness of stem cell therapy during the acute phase of stroke, however the chronic phase presents more of a challenge as the BBB has reduced permeability during this phase. This study showed that mannitol managed to induce BBB permeability during the chronic phase and augment the therapeutic effects of stem cell therapy.
Their study will be published in a future issue of the journal Cell Transplantation and is currently freely available on-line as an unedited, early epub at: http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-CT-1550_Tajiri_et_al
“Finding an effective stroke treatment has been a significant challenge,” explained Dr. Cesar V. Borlongan, distinguished professor and director of the Center of Excellence for Aging and Brain Repair in the Department of Neurosurgery and Brain Repair at the University of South Florida, Tampa, FL. “Current anti-blood clot treatment with tissue plasminogen activator (tPA) can only be used in a small window in the acute stage of stroke within four hours after a stroke has occurred, which means that only a small number of stroke patients can receive this treatment. The relative impermeability of the BBB to stem cells has been a hurdle and has required the use of large numbers of stem cells. This is particularly true during the chronic phase of stroke.”
This study on animal models using transplanted human umbilical cord cells demonstrated that stem cell transplantation improved behavioral and functional benefits when the cells passed through the BBB with the assistance of a mannitol carrier when compared to a control group, also modeled with stroke that received stem cells alone. The researchers also documented the enhancement of neural cell growth for the animals in the mannitol arm of the study.
According to the researchers, the study demonstrated that the required therapeutic number of stem cells for effective delivery was reduced 10-fold when using mannitol as a transport “vehicle.” The low dose has the advantage of providing increased safety for patients who could experience microembolism with large stem cell doses.
The reduction in the therapeutic dose of stem cells means that patients could have repeated stem cell administrations in both the acute phase and chronic phase of stroke, concluded the researchers.
“The use of mannitol is an innovative solution for stem cell therapy and may serve to allay concerns related to high doses of stem cells, that may cause embolisms,” said Dr. Shinn-Zong (John) Lin, professor of Neurosurgery at China Medical University Hospital in TaiChung, Taiwan and Co-Editor-in-Chief for Cell Transplantation. “This promising approach should be tested further to validate safety and efficacy preclinically and then clinically.”
The study was funded by NIH R01NS071956, NIH R01 NS090962, NIH R21NS089851, NIH R21 NS094087, DOD W81XWH-11-1-0634, and VA Merit Review I01 BX001407.