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Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1+ stem cells from young donors.
Journal of Neuroinflammation ( IF 9.3 ) Pub Date : 2020-02-07 , DOI: 10.1186/s12974-019-1681-3
Lukasz Wlodarek 1, 2 , Feng Cao 2, 3 , Faisal J Alibhai 1 , Adam Fekete 3 , Nima Noyan 1 , Stephanie W Tobin 1 , Tina B Marvasti 1, 4 , Jun Wu 1 , Shu-Hong Li 1 , Richard D Weisel 1, 4, 5 , Lu-Yang Wang 2, 3 , Zhengping Jia 2, 3 , Ren-Ke Li 1, 2, 4, 5
Affiliation  

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.

中文翻译:

通过年轻供体的重组Sca-1 +干细胞纠正老年小鼠的放疗引起的认知障碍。

背景技术放射疗法被广泛用于治疗脑肿瘤并且有效,但是由于其阻止了对学习和记忆重要的细胞过程,因此不可避免地损害了认知。这在再生能力有限的衰老大脑中尤为明显,因为辐射会产生无法修复的神经元损伤并激活邻近的小胶质细胞。后者导致神经元死亡增加,并导致治疗后认知能力下降。迄今为止,几乎没有有效的方法可以防止放疗后的认知缺陷。方法在这里,我们将表达绿色荧光蛋白(GFP)的年轻或年老(分别为2个月或18个月大)供体小鼠的造血干细胞(HSC)植入到年老受体中,并在重建后3个月评估了认知能力。结果无论捐赠者年龄如何,GFP +细胞归巢于老受体的大脑,并表达巨噬细胞/微胶质标记物Iba1。但是,只有年轻的细胞才能减轻新对象识别和空间记忆以及辐射后老年小鼠学习中的缺陷。从机制上讲,接受年轻HSC但不接受老年HSC的老受体在海马CA1神经元中显示出明显更高的树突棘密度和长期增强(LTP)。最后,我们发现来自年轻和老供体的GFP + / Iba1 +细胞被差异极化为抗炎和促炎表型,并分别在体内产生神经保护因子和活性氮。结论我们的研究结果表明,老化的外周小胶质细胞样细胞可能在放疗后加重认知障碍,而年轻的小胶质细胞样细胞在受辐照的大脑中极化为修复表型,特别是在与奖励,学习和记忆相关的神经回路中。这些发现提供了原理上的证明,可以有效地恢复来自年轻供体骨髓的外周干细胞对辐照后大脑的中枢认知功能。
更新日期:2020-02-07
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