Grafting Neural Stem and Progenitor Cells Into the Hippocampus of Juvenile, Irradiated Mice Normalizes Behavior Deficits

Abstract

The pool of neural stem and progenitor cells (NSPCs) in the dentate gyrus of the hippocampus is reduced by ionizing radiation. This explains, at least partly, the learning deficits observed in patients after radiotherapy, particularly in pediatric cases. An 8 Gy single irradiation dose was delivered to the whole brains of postnatal day 9 (P9) C57BL/6 mice, and BrdU-labeled, syngeneic NSPCs (1.0 × 105 cells/injection) were grafted into each hippocampus on P21. Three months later, behavior tests were performed. Irradiation impaired novelty-induced exploration, place learning, reversal learning, and sugar preference, and it altered the movement pattern. Grafting of NSPCs ameliorated or even normalized the observed deficits. Less than 4% of grafted cells survived and were found in the dentate gyrus 5 months later. The irradiation-induced loss of endogenous, undifferentiated NSPCs in the dentate gyrus was completely restored by grafted NSPCs in the dorsal, but not the ventral, blade. The grafted NSPCs did not exert appreciable effects on the endogenous NSPCs; however, more than half of the grafted NSPCs differentiated. These results point to novel strategies aimed at ameliorating the debilitating late effects of cranial radiotherapy, particularly in children.

Metformin pretreatment rescues olfactory memory associated with subependymal zone neurogenesis in a juvenile model of cranial irradiation

“…Herein, we investigated the effects of metformin pretreatment (preTx) in a model of juvenile cranial IR 8 that involves a clinically relevant dose of IR (8 Gy) 45 and age (postnatal day 17 [P17]). 5 , 46 Using an in vitro NSC colony-forming assay (neurosphere assay), we assessed the effects of metformin preTx and cranial IR on the activated NSC (aNSC) pool (i.e., colony-forming NSCs in vitro ) 47 and quantified neurogenesis and microglia activation along the SEZ-OB neurogenic axis in vivo .…”

IntelliCage: the development and perspectives of a mouse- and user-friendly automated behavioral test system

“…Yet they showed again that the IntelliCages were able to recognize systematic group effects in partially noisy and uncontrollable environments. Of note, however, is that IntelliCages were used later to reveal irradiation-induced behavioral changes ( Barlind et al, 2010 ; Karlsson et al, 2011 ; Huo et al, 2012 ; Roughton et al, 2012 ; Ben Abdallah et al, 2013 ; Kalm et al, 2013 , 2016 ; Osman et al, 2014 ; Kato et al, 2018 ; Sato et al, 2018 ).…”

Umbilical cord blood stem cell therapy in premature brain injury: Opportunities and challenges

“…It has been shown that UCB‐SC treatment plays a neural‐restorative and neural‐regenerative role in premature brain injuries (Sun & Kurtzberg, ) (Figure ). Some UCB‐SCs likely differentiate into “replacement” glial cells and neurons and integrate into the host brain where they play a role in re‐myelination (Sato et al, ; Shen et al, ). In addition, UCB‐SCs might enhance blood vessel regeneration (Kourembanas, ), and an increasing number of studies have indicated that UCB‐SCs migrating to the site of brain injury might provide restorative and neuroprotective factors or endogenous cell signals to injured host neural cells via the paracrine activity of immune factors, anti‐inflammatory cytokines such as IL‐8 and IL‐10 (Nazmi et al, ; Xia et al, ), and neurotrophic factors such as neurotrophin‐3/4, brain‐derived neurotrophic factors, glial‐derived neurotrophic factor, vascular endothelial growth factor, hepatocyte growth factor, and insulin‐like growth factor‐1, which support neuronal migration, proliferation, and differentiation and promote angiogenesis (Bennet et al, ; Drobyshevsky et al, ; Geisler, Dinse, Neuhoff, Kreikemeier, & Meier, ; Hellstrom et al, ; Rosenkranz & Meier, ).…”