Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain

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 headonly 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.radiation-induced cognitive dysfunction | microvesicles | dendritic complexity | human neural stem cells | neuroinflammation W ith improved diagnosis and treatment, cancer survivorship continues to rise but often at the cost of quality of life. The unintended neurocognitive sequelae resulting from cranial irradiation used to treat primary and secondary malignancies of the brain are both progressive and debilitating (1, 2). Despite the recognition and prevalence of these adverse side effects, relatively few, if any, long-term satisfactory solutions exist for this unmet medical need. Past work from our laboratory has optimized transplantation parameters and established many of the long-term benefits of human stem cell-based therapies for the treatment of radiationinduced cognitive dysfunction (3-5). Cranially grafted stem cells have been shown to impart persistent improvements in behavioral performance in irradiated rats over extended postirradiation intervals (1-8 mo) using short-and long-term cognitive testing paradigms (4, 6, 7). These studies have shown that our stem cell-based approaches improve the functional plasticity of the host brain through a variety of mechanisms including (i) the suppression of neuroinflammation (5), (ii) the addition of new cells to active hippocampal circuits (4), and (iii) a long-term trophic support mechanism that facilitates the expression of activity-regulated cytoskeletonassociated protein that functions in multiple ways as a molecular determinant of memory (7). Moreover, using a distinctly different injury paradigm, stem cell grafting pres...

Stem Cell Therapies for the Resolution of Radiation Injury to the Brain

“…To circumvent such caveats, work by Baulch et al . demonstrated the promise of using transplanted human neural stem cell-derived microvesicles, in place of stem cells [48]. Intrahippocampal grafting of microvesicles ameliorated the cognitive decrements associated with cranial radiation exposure, decreased neuroinflammation, and preserved dendritic morphology in rats.…”

“…Intrahippocampal grafting of microvesicles ameliorated the cognitive decrements associated with cranial radiation exposure, decreased neuroinflammation, and preserved dendritic morphology in rats. The transplanted microvesicles were found to migrate throughout the hippocampus and fuse with host brain cells, as determined by tracking a fluorescent marker protein expressed on the surface of the grafted microvesicles [48]. The foregoing data provided some provocative insight into the mechanisms of cognitive improvement following irradiation, and suggested that the bioactive cargo within microvesicles conferred neurotrophic support to the host brain.…”

Cellular Therapies for Treatment of Radiation Injury: Report from a NIH/NIAID and IRSN Workshop

“…These grafts led to improved performance on behavioral tasks, as well as a reduction in inflammation and retention in neuronal morphology (134). Exosome grafting has led to similar improvements (135). …”

The Emerging Role of Cell-Derived Microvesicles in Stem Cell Research and Therapy

“…In another milestone study, Ratajczak et al showed that MVs from ESCs can reprogram hematopoietic stem cells and increase their pluripotency through horizontal transfer of mRNAs [3]. In addition to ESCs, human neural stem cells can generate MVs that have neurocognitive benefits and ameliorate radiation-induced cognitive deficits brought on during radio-and chemo-therapeutic treatment of brain cancers [15].…”