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Microvesicles for brain radiation recovery?

Stem cells show promise for treating brain regions damaged by cancer radiation treatment. Now, research has found microscopic vesicles give similar benefit without some stem cell associated risks.


Microvesicles (cMVs) are small, fluid-filled sacs secreted by all human cells. These membrane wrapped fragments are between 50 and 1,000 nanometers (nm) in diameter and found in many types of body fluids as well as the spaces between cells. Though initially thought of as cell debris, cMVs play a role in cell signaling and molecular communication between cells. They each contain a variety of proteins, RNAs, and more, that benefit cells. In the brain, they help regulate neuron health/function, while also playing a role in tissue regeneration.

In research with rats, microvesicles that were transplanted two days after skull radiation, were found to restore cognitive function, reduce inflammation and protect neurons as measured at four and six week post radiation treatment. These improvements were seen with no signs of rejection or tumor growth, which are two stem cell-related risk factors.


Brain tumors are always limited by how well healthy tissue tolerates radiation therapy.

"In almost every instance, people experience severe cognitive impairment that's progressive and debilitating. Pediatric cancer patients can experience a drop of up to three IQ points per year."

Charles L. Limoli PhD, Professor, Department of Radiation Oncology,  School of Medicine, University of California, Irvine, CA, USA


At the University of California at Irvine (UCI) research, Charles Limoli along with colleagues, isolated and removed cMVs secreted by human neural stem cells from healthy rats. These cMVs were then transplanted into the brains of rats which had undergone cranial radiation therapy. The injections above their hippocampus — a region known for growth of new neurons — each contained 2 microliters of cMVs.


One month following irradiation, rats that received microvesicle (cMV) injections showed significant improvements in cognition measured by four behavior tasks. These benefits were found with considerable reduction in neuroinflammation and the preservation of neuronal structures — both classic signs radiation injury in the brain was either prevented or reversed.


Limoli reported similar results from a 2011 study in which multipotent human neural stem cells were used. However, stem cells may present certain risks, such as rejection by the body's immune system, which can increase existing tumor size or transform them into teratomas. These conditions are less likely with microvesicles.

Limoli: "The appeal of strategies using microvesicles instead of stem cells is that they eliminate any concern for teratoma formation and substantially minimize side effects associated with immune system rejection."

He adds that future work is needed to identify the specific factors within microvesicles responsible for these protective qualities, as well as to determine how long these beneficial effects persist.

Significance
Cranial irradiation used during the clinical management of brain cancer is associated with severe cognitive decline and represents a particular concern for pediatric cancer survivors. Irradiation triggers neuroinflammation and compromises the structure of neurons, factors that are contributory if not causal to radiation-induced cognitive dysfunction. Our previous data have shown that intra-hippocampal transplantation of human neural stem cells (hNSCs) could ameliorate radiation-induced behavioral deficits and improve neuronal plasticity. These beneficial neurocognitive effects were hypothesized to act through a trophic support mechanism involving the secretion of microvesicles acting on host neuronal circuitry. Here we show that cranial grafting of hNSC-derived microvesicles reverses or prevents radiation-induced cognitive dysfunction through mechanisms involving the suppression of inflammation and the preservation of host neuronal architecture.

Abstract
Cancer survivors face a variety of challenges as they cope with disease recurrence and a myriad of normal tissue complications brought on by radio- and chemotherapeutic treatment regimens. For patients subjected to cranial irradiation for the control of CNS malignancy, progressive and debilitating cognitive dysfunction remains a pressing unmet medical need. Although this problem has been recognized for decades, few if any satisfactory long-term solutions exist to resolve this serious unintended side effect of radiotherapy. Past work from our laboratory has demonstrated the neurocognitive benefits of human neural stem cell (hNSC) grafting in the irradiated brain, where intrahippocampal transplantation of hNSC ameliorated radiation-induced cognitive deficits. Using a similar strategy, we now provide, to our knowledge, the first evidence that cranial grafting of microvesicles secreted from hNSC affords similar neuroprotective phenotypes after head-only irradiation. Cortical- and hippocampal-based deficits found 1 mo after irradiation were completely resolved in animals cranially grafted with microvesicles. Microvesicle treatment was found to attenuate neuroinflammation and preserve host neuronal morphology in distinct regions of the brain. These data suggest that the neuroprotective properties of microvesicles act through a trophic support mechanism that reduces inflammation and preserves the structural integrity of the irradiated microenvironment.

Authors: Janet Baulch, Munjal Acharya, Barrett Allen, Ning Ru, Nicole Chmielewski, Erich Giedzinski, Amber Syage, Audrey Park, Sarah Benke and Vipan Parihar of the UCI Department of Radiation Oncology in the School of Medicine contributed to the study. The work received support from the Defense Threat Reduction Agency, the American Cancer Society, NASA, the National Institutes of Health and the UCI Institute for Clinical & Translational Science

About the University of California, Irvine: Currently celebrating its 50th anniversary, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 30,000 students and offers 192 degree programs. It's located in one of the world's safest and most economically vibrant communities and is Orange County's second-largest employer, contributing $4.8 billion annually to the local economy. For more on UCI, visit http://www.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UC Irvine faculty and experts, subject to availability and university approval. For more UC Irvine news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

The project was funded by:
Defense Threat Reduction Agency, American Cancer Society, NASA, National Institutes of Health, UCI Institute for Clinical & Translational Science
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Apr 19, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   


Microvesicles (cMVs) are small, fluid-filled sacs secreted by all human cells.
Image Credit: Circulation Research American Heart Association


 

 


 

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