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

Autor: Wlodarek L; Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada.; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada., Cao F; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.; Program in Neurosciences & Mental Health, SickKids Research Institute, Floor 5, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada., Alibhai FJ; Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada., Fekete A; Program in Neurosciences & Mental Health, SickKids Research Institute, Floor 5, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada., Noyan N; Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada., Tobin SW; Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada., Marvasti TB; Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada.; Faculty of Medicine, Institute of Medical Science, University of Toronto, Toronto, ON, Canada., Wu J; Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada., Li SH; Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada., Weisel RD; Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada.; Faculty of Medicine, Institute of Medical Science, University of Toronto, Toronto, ON, Canada.; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada., Wang LY; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. luyang.wang@utoronto.ca.; Program in Neurosciences & Mental Health, SickKids Research Institute, Floor 5, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. luyang.wang@utoronto.ca., Jia Z; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. zhengping.jia@sickkids.ca.; Program in Neurosciences & Mental Health, SickKids Research Institute, Floor 5, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. zhengping.jia@sickkids.ca., Li RK; Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada. renkeli@uhnresearch.ca.; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. renkeli@uhnresearch.ca.; Faculty of Medicine, Institute of Medical Science, University of Toronto, Toronto, ON, Canada. renkeli@uhnresearch.ca.; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada. renkeli@uhnresearch.ca.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2020 Feb 07; Vol. 17 (1), pp. 51. Date of Electronic Publication: 2020 Feb 07.
DOI: 10.1186/s12974-019-1681-3
Abstrakt: Background: 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 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.
Methods: Here 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.
Results: Regardless 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.
Conclusion: Our 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.
Databáze: MEDLINE
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