Abstract
Manganese (Mn) is a potent neurotoxin known to cause long-lasting structural damage and progressive cognitive deficits in the brain. However, new therapeutic approaches are urgently needed since current treatments only target symptoms of Mn exposure. Recent studies have suggested a potential role for multipotent neural stem cells (NSCs) in the etiology of Mn-induced cognitive deficits. In this study, we evaluated the effect of direct intracerebral transplantation of NSCs on cognitive function of mice chronically exposed to MnCl2, and further explored the distribution of transplanted NSCs in brain tissues. NSCs were isolated and bilaterally injected into the hippocampal regions or lateral ventricles of Mn-exposed mice. The results showed that many transplanted cells migrated far away from the injection sites and survived in vivo in the Mn-exposed mouse brain, implying enhanced neurogenesis in the host brain. We found that NSCs transplanted into either the hippocampal regions or the lateral ventricles significantly improved spatial learning and memory function of the Mn-exposed mice in the Morris water maze. Immunofluorescence analyses indicated that some surviving NSCs differentiated into neurons or glial cells, which may have become functionally integrated into the impaired local circuits, providing a possible cellular basis for the improvement of cognitive function in NSC-transplanted mice. Taken together, our findings confirm the Mn-induced impairment of neurogenesis in the brain and underscore the potential of treating Mn exposure by NSC transplantation, providing a practical therapeutic strategy against this type of neurotoxicity.
Highlights
Manganese (Mn) is a potent neurotoxin known to cause long-lasting structural damage and progressive cognitive deficits in the brain
A recent study using synchrotron X-ray fluorescence (XRF) microscopy revealed that the hippocampal dentate gyrus (DG) and CA3 area were the regions with the greatest accumulation of Mn in Mn-exposed rats [13]. and several recent reports have identified the hippocampus as one of the key brain areas affected by Mn toxicity [14], where the metal has been found to selectively accumulate
We and others have previously detected a decrease in the proliferation of multipotent neural stem cells (NSCs) within the hippocampal subgranular zone (SGZ) that was suggestive of disrupted neurogenesis that closely coincided with deficits in spatial recognition
Summary
Manganese (Mn) is a potent neurotoxin known to cause long-lasting structural damage and progressive cognitive deficits in the brain. Converging evidence has shown that NSCs in the brain undergoing differentiation and maturation play important roles in learning and memory functions [19, 21], suggesting the potential of NSC transplantation as a promising tool to compensate for neuronal loss and structural damage in the adult hippocampus [20]. This would provide an indispensable source of new cells to support neuroplasticity and granule cell turnover that could lead to recovery from cognitive impairments [22, 23]. The results described here provide a rationale for further investigation of NSCs for the treatment of heavy metal-induced toxic encephalopathies associated with impaired neurogenesis and neurobehavioral deficits
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