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Functional Equivalence of Stem Cell and Stem Cell-Derived Extracellular Vesicle Transplantation to Repair the Irradiated Brain.

Authors
  • Smith, Sarah M1
  • Giedzinski, Erich1
  • Angulo, Maria C1
  • Lui, Tiffany1
  • Lu, Celine1
  • Park, Audrey L1
  • Tang, Sharon1
  • Martirosian, Vahan1
  • Ru, Ning1
  • Chmielewski, Nicole N1
  • Liang, Yaxuan1
  • Baulch, Janet E1
  • Acharya, Munjal M1
  • Limoli, Charles L1
  • 1 Department of Radiation Oncology, University of California, Irvine, California, USA.
Type
Published Article
Journal
Stem Cells Translational Medicine
Publisher
Wiley (John Wiley & Sons)
Publication Date
Sep 30, 2019
Identifiers
DOI: 10.1002/sctm.18-0227
PMID: 31568685
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Cranial radiotherapy, although beneficial for the treatment of brain tumors, inevitably leads to normal tissue damage that can induce unintended neurocognitive complications that are progressive and debilitating. Ionizing radiation exposure has also been shown to compromise the structural integrity of mature neurons throughout the brain, an effect believed to be at least in part responsible for the deterioration of cognitive health. Past work has shown that cranially transplanted human neural stem cells (hNSCs) or their extracellular vesicles (EVs) afforded long-term beneficial effects on many of these cognitive decrements. To provide additional insight into the potential neuroprotective mechanisms of cell-based regenerative strategies, we have analyzed hippocampal neurons for changes in structural integrity and synaptic remodeling after unilateral and bilateral transplantation of hNSCs or EVs derived from those same cells. Interestingly, hNSCs and EVs similarly afforded protection to host neurons, ameliorating the impact of irradiation on dendritic complexity and spine density for neurons present in both the ipsilateral and contralateral hippocampi 1 month following irradiation and transplantation. These morphometric improvements were accompanied by increased levels of glial cell-derived growth factor and significant attenuation of radiation-induced increases in postsynaptic density protein 95 and activated microglia were found ipsi- and contra-lateral to the transplantation sites of the irradiated hippocampus treated with hNSCs or hNSC-derived EVs. These findings document potent far-reaching neuroprotective effects mediated by grafted stem cells or EVs adjacent and distal to the site of transplantation and support their potential as therapeutic agents to counteract the adverse effects of cranial irradiation. Stem Cells Translational Medicine2019. © 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

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