Abstract
We previously demonstrated that transplantation of murine neural stem cells (NSCs) can improve motor and cognitive function in a transgenic model of Dementia with Lewy Bodies (DLB). These benefits occurred without changes in human α-synuclein pathology and were mediated in part by stem cell-induced elevation of brain–derived neurotrophic factor (BDNF). However, instrastriatal NSC transplantation likely alters the brain microenvironment via multiple mechanisms that may synergize to promote cognitive and motor recovery. The underlying neurobiology that mediates such restoration no doubt involves numerous genes acting in concert to modulate signaling within and between host brain cells and transplanted NSCs. In order to identify functionally connected gene networks and additional mechanisms that may contribute to stem cell-induced benefits, we performed weighted gene co-expression network analysis (WGCNA) on striatal tissue isolated from NSC- and vehicle-injected wild-type and DLB mice. Combining continuous behavioral and biochemical data with genome wide expression via network analysis proved to be a powerful approach; revealing significant alterations in immune response, neurotransmission, and mitochondria function. Taken together, these data shed further light on the gene network and biological processes that underlie the therapeutic effects of NSC transplantation on α-synuclein induced cognitive and motor impairments, thereby highlighting additional therapeutic targets for synucleinopathies.
Highlights
For the great majority of neurodegenerative diseases, neuronal damage and loss occur long before clinical symptoms first become apparent [79, 102]
We previously demonstrated that transplantation of murine neural stem cells (NSCs) leads to significant improvements in both motor and cognitive function in a transgenic model of Dementia with Lewy Bodies (DLB) [41]
Since the network construction and correlational analysis were conducted in a blinded manner, we first performed gene set enrichment analysis (GSEA) to address whether the modules were differentially expressed in Overexpressed wild-type human α-synuclein (ASO) mice in response to Vehicle or NSC treatment
Summary
For the great majority of neurodegenerative diseases, neuronal damage and loss occur long before clinical symptoms first become apparent [79, 102] For this reason therapies designed to target upstream pathological initiators of disease have far failed in clinical trials of symptomatic patients [30, 90] In contrast, the emerging field of stem cell transplantation may offer a Lakatos et al Acta Neuropathologica Communications (2017) 5:21. We found that NSCs could significantly improve both motor and cognitive function 1 month after transplantation into the striata of aged ASO mice. These benefits, were not accompanied by any changes in Lewy body-like α-synuclein inclusions. In order to identify these other potential regulatory networks involved in NSC-induced functional recovery, we have examined whole genome gene expression in striatal samples isolated from these same mice [41]
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