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.
Highlights
Brain cancer remains one of the leading causes of death worldwide [1]
bone marrow (BM) cells which arise from Stem cell antigen-1 (Sca-1)+ stem cells migrate to the brain and give rise to Iba1+ cells Stem cell therapies using cell transplantation for the repair and regeneration of brain tissue have been previously demonstrated to elicit beneficial effects; the positive effects are short-lived due to rapid loss of transplanted cells [30]
In the absence of pro-inflammatory Iba1+ cells, which become polarized to this state if they are derived from old Sca-1+ stem cells, do the animals display significant long-term improvements in hippocampal-dependent learning and memory following irradiation
Summary
Brain cancer remains one of the leading causes of death worldwide [1]. Current treatments using radiation are effective when applied with spatiotemporal control, and lead to cognitive complications that arise later in life [2, 3]. Microglial cells in the young brain are not polarized to an inflammatory phenotype Instead, they secrete neurotrophic factors which regulate neuronal function and repair processes [9, 10]. Radiotherapy 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 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. There are few effective means to prevent cognitive deficits after radiotherapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
