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Functional, Safe, and Effective Mitigation of Radiation-Induced Cognitive Deficits Using Stem Cell-Derived Extracellular Vesicles in a Wild-Type Rodent Model

  • Author(s): Leavitt, Ron Joshua
  • Advisor(s): Limoli, Charles L
  • et al.

Radiation-induced learning and memory problems are reported in more than half of survivors of cancers treated with cranial radiotherapy, representing an unmet clinical need in a growing population. Cell-free therapy employing extracellular vesicles (EV) derived from stem cells has been pioneered to address this problem in an immunocompromised rodent model. However, no study has yet demonstrated efficacy of this cell-free treatment in wild-type animals or determined the mechanism. This research has sought to address both of those shortcomings, as well as introduce a more clinically palatable delivery method to improve safety while maintaining efficacy.

A large cohort of wild-type mice was used to determine the efficacy of post-irradiation EV treatment in wild-type animals and retro-orbital sinus injection. At five weeks and six months post-irradiation, animals were subjected to a battery of cognitive behavioral tests. Follow up studies analyzed tissues via RNA-seq, RT-qPCR, and immunohistochemical staining. Behavioral testing demonstrated that radiation-induced cognitive dysfunction (RICD) was ameliorated at both five weeks and six months post-irradiation following a single dose of human neural stem cell-derived EV delivered either directly into the hippocampus or using the new indirect (retro-orbital) method. Microglial activation (neuroinflammation) in the hippocampus was also mitigated by EV treatment at both time-points.

RNA-seq revealed inflammatory processes to be important and pointed toward miR-124 as a possible functional component of the EV bioactive cargo. To determine mechanistic importance, miR-124 overexpression in the brain was achieved using an adeno-associated virus delivered directly to the hippocampus. miR-124 overexpression also showed mitigation of RICD in behavioral testing. Expression analysis showed multiple common differentially expressed genes with the RNA-seq data set.

Mitigation of RICD and neuroinflammation was shown in wildtype animals for the first time. Retro-orbital sinus delivery was shown to be safe and effective in this application. The candidate for active EV cargo (miR-124) was also found to be sufficient for mitigation of RICD. Expression data supported a role for miR-124-dependent modulation of the DNA-damage response and microglial regulation (via Cepba and PU.1/Spi1).

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