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Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1+ stem cells from young donors

Authors
  • Wlodarek, Lukasz1, 2
  • Cao, Feng2, 3
  • Alibhai, Faisal J.1
  • Fekete, Adam3
  • Noyan, Nima1
  • Tobin, Stephanie W.1
  • Marvasti, Tina B.1, 2
  • Wu, Jun1
  • Li, Shu-Hong1
  • Weisel, Richard D.1, 2, 2
  • Wang, Lu-Yang2, 3
  • Jia, Zhengping2, 3
  • Li, Ren-Ke1, 2, 2, 2
  • 1 University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada , Toronto (Canada)
  • 2 University of Toronto, Toronto, ON, Canada , Toronto (Canada)
  • 3 Program in Neurosciences & Mental Health, SickKids Research Institute, Floor 5, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada , Toronto (Canada)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Feb 07, 2020
Volume
17
Issue
1
Identifiers
DOI: 10.1186/s12974-019-1681-3
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundRadiotherapy is widely used and effective for treating brain tumours, but inevitably impairs cognition as it arrests cellular processes important for learning and memory. This is particularly evident in the aged brain with limited regenerative capacity, where radiation produces irreparable neuronal damage and activation of neighbouring microglia. The latter is responsible for increased neuronal death and contributes to cognitive decline after treatment. To date, there are few effective means to prevent cognitive deficits after radiotherapy.MethodsHere we implanted hematopoietic stem cells (HSCs) from young or old (2- or 18-month-old, respectively) donor mice expressing green fluorescent protein (GFP) into old recipients and assessed cognitive abilities 3 months post-reconstitution.ResultsRegardless of donor age, GFP+ cells homed to the brain of old recipients and expressed the macrophage/microglial marker, Iba1. However, only young cells attenuated deficits in novel object recognition and spatial memory and learning in old mice post-irradiation. Mechanistically, old recipients that received young HSCs, but not old, displayed significantly greater dendritic spine density and long-term potentiation (LTP) in CA1 neurons of the hippocampus. Lastly, we found that GFP+/Iba1+ cells from young and old donors were differentially polarized to an anti- and pro-inflammatory phenotype and produced neuroprotective factors and reactive nitrogen species in vivo, respectively.ConclusionOur results suggest aged peripherally derived microglia-like cells may exacerbate cognitive impairments after radiotherapy, whereas young microglia-like cells are polarized to a reparative phenotype in the irradiated brain, particularly in neural circuits associated with rewards, learning, and memory. These findings present a proof-of-principle for effectively reinstating central cognitive function of irradiated brains with peripheral stem cells from young donor bone marrow.

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