Low-Dose Radiation Stimulates Wnt/β-Catenin Signaling, Neural Stem Cell Proliferation and Neurogenesis of the Mouse Hippocampus in vitro and in vivo

Abstract

Neurogenesis in the hippocampus is actively involved in neural circuit plasticity and learning function of mammals, but it may decrease dramatically with aging and aging-related neurodegenerative disorder Alzheimer's disease. Accumulating studies have indicated that Wnt/β-catenin signaling is critical in control of proliferation and differentiation fate of neural stem cells or progenitors in the hippocampus. In this study, the biological effects of low-dose radiation in stimulating Wnt/β-catenin signaling, neural stem cell proliferation and neurogenesis of hippocampus were interestingly identified by in vitro cell culture and in vivo animal studies. First, low-dose radiation (0.3Gy) induced significant increasing of Wnt1, Wnt3a, Wnt5a, and β-catenin expression in both neural stem cells and in situ hippocampus by immunohistochemical and PCR detection. Secondly, low-dose radiation enhanced the neurogenesis of hippocampus indicated by increasing proliferation and neuronal differentiation of neural stem cells, going up of nestin-expressing cells and BrdU-incorporation in hippocampus. Thirdly, it promoted cell survival and reduced apoptotic death of neuronal stem cells by flowcytometry analysis. Finally, Morris water-maze test showed behavioral improvement of animal learning in low-dose radiation group. Accordingly, detrimental influence on Wnt/β-catenin signaling or neurogenesis was confirmed in high-dose radiation (3.0Gy) group. Taken together, this study has revealed certain beneficial effects of low-dose radiation to stimulate neural stem cell proliferation, the neurogenesis of hippocampus and animal learning most possibly by triggering Wnt/β-catenin signaling cascades, suggesting its translational application role in devising new therapy for aging-related neurodegenerative disorders particularly Alzheimer's disease.

Radiation responses of stem cells: targeted and non-targeted effects

“…Low dose IR does not appear to cause an increase in cell death (60,66) , but increased proliferation has been observed in several studies. Liang et al (2011) found a significant increase in proliferation of rat MSC at 50 and 75 mGy (67) .…”

“…However, increases in proliferation at 20 mGy and 100 mGy failed to reach significance, indicating a non-linear response (67) . In vivo studies have also found increased proliferation, in both HSCs in (75 mGy) (68) and neural stem cells (NSC) (300 mGy) (66) . Bakinskis et al (2011) found an increase in proliferation proteins in murine NSC, but no increase in proliferation rate (69) .…”

“…Bakinskis et al (2011) found an increase in proliferation proteins in murine NSC, but no increase in proliferation rate (69) . Wei et al (2012) suggested that increased proliferation at low doses (300 mGy) was due to an increase in Wnt/β-catenin signalling, which was not seen at moderate (3Gy) doses (66) . This contradicts Wilson et al (2010) who found increased Wnt/β-catenin signalling in 2 Gy irradiated cells, but not in 400 mGy irradiated cells.…”

Low dose effects of ionizing radiation on normal tissue stem cells

“…Radiation induced stimulation of wound healing was connected to a timedependent gradual increase in the number of bone marrow and circulating stem cells detected. In addition, flow cytometry analyses revealed reduced apoptosis and improved cell survival of the neuronal stem cells [94]. Table 1 In the last three sections there was given an overview of the current knowledge about radiation-induced effects on normal stem cells and the responses to different radiation doses.…”

Low Dose Radiation Adaptive Protection to Control Neurodegenerative Diseases

“…This has been studied in a mouse model. LDR has been shown to stimulate neural stem cell proliferation, which resulted in neurogenesis in the hippocampus and led to improved animal learning (Wei et al, 2012). LDR also resulted in improved retinal thickness in a mouse model of retinal neurodegeneration (Otani et al, 2012).…”