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Human mesenchymal stem cells prevent neurological complications of radiotherapy

ABSTRACT: Radiotherapy is a highly effective tool for the treatment of brain cancer. However, radiation also causes detrimental effects in the healthy tissue, leading to neurocognitive sequelae that compromise the quality of life of brain cancer survivors. Despite the recognition of this serious complication, no satisfactory solutions exist at present. Here we investigated the effects of intranasal administration of human mesenchymal stem cell (hMSCs) as a neuroprotective strategy for cranial radiation in mice. Our results demonstrated that intranasally delivered hMSCs promote radiation-induced brain injury repair, improving neurological function. The molecular analysis revealed that hMSC administration reduces persistent activation of damage-induced c-AMP response element-binding signaling in the irradiated neurogenic niches. Furthermore, hMSC treatment did not compromise survival of glioma-bearing mice. Our findings encourage the therapeutic use of hMSCs as an effective and non-invasive approach to prevent neurological complications of radiotherapy, improving the quality of life of brain tumor survivors.

ORGANISM(S): Mus musculus

PROVIDER: GSE115735 | GEO | 2019/06/21

REPOSITORIES: GEO

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Project description:The methodology for the repair of critical-sized or non-union bone lesions has unpredictable efficacy due in part to our incomplete knowledge of bone repair and the biocompatibility of bone substitutes. Although human mesenchymal stem cells (hMSCs) differentiate into osteoblasts, which promote bone growth, their ability to repair bone has been unpredictable. We hypothesized that given the multi-stage process of osteogenesis, hMSC-mediated repair might be maximal at a specific time-point of healing. Utilizing a mouse model of calvarial healing, we demonstrate that the osteo-repair capacity of hMSCs can be substantially augmented by treatment with an inhibitor of peroxisome-proliferator-activated-receptor-γ, but efficacy is confined to the rapid osteogenic phase. Upon entry into the bone-remodeling phase, hMSC retention signals are lost, resulting in truncation of healing. To solve this limitation, we prepared a scaffold consisting of hMSC-derived extracellular matrix (ECM) containing the necessary biomolecules for extended site-specific hMSC retention. When inhibitor-treated hMSCs were co-administered with ECM, they remained at the injury well into the remodeling phase of healing, which resulted in reproducible and complete repair of critical-sized defects in 3 weeks. These data suggest that hMSC-derived ECM and inhibitor-treated hMSCs could be employed at optimal times to substantially and reproducibly improve bone repair. To gain insight into the superior healing potential of GW-hMSCs and also what might be accounting for their extended engraftment, microarray analyses on the RNA extracted from the calvarial tissue recovered after days 5 and 14 were performed. Equal amounts of total RNA from 4 animals per group and time point were pooled and animals receiving control (DMSO) or peroxisome proliferator-activated receptor-gamma inhibitor GW9662-treated hMSCs were compared with the assumption that murine cross-hybridization would be constant throughout the samples and thus be subtracted from the analysis.

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Human mesenchymal stem cells prevent neurological complications of radiotherapy

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