Abstract
BackgroundNeural stem cell (NSC)-based therapies hold great promise for treating diseases of the central nervous system (CNS). However, several fundamental problems still need to be overcome to fully exploit the clinical potential of NSC therapeutics. Chief among them is the limited survival of NSC grafts within hostile microenvironments.MethodsHerein, we sought to engineer NSCs in an effort to increase graft survival within ischemic brain lesions via upregulation of global SUMOylation, a post-translational modification critically involved in mediating tolerance to ischemia/reperfusion.FindingsNSCs overexpressing the SUMO E2-conjugase Ubc9 displayed resistance to oxygen-glucose-deprivation/restoration of oxygen/glucose (OGD/ROG) and enhanced neuronal differentiation in vitro, as well as increased survival and neuronal differentiation when transplanted in mice with transient middle cerebral artery occlusion in vivo.InterpretationOur work highlights a critical role for SUMOylation in NSC biology and identifies a biological pathway that can be targeted to increase the effectiveness of exogenous stem cell medicines in ischemic stroke.FundIntramural Research Program of the NINDS/NIH, the Italian Multiple Sclerosis Foundation (FISM), the Bascule Charitable Trust, NIH-IRTA-OxCam and Wellcome Trust Research Training Fellowships.
Highlights
In ischemic stroke a crisis in energy availability due to the sudden reduction of oxygen and glucose leads to the depletion of cellular energy stores, aberrant neurotransmitter release, and intense cytotoxic/inflammatory responses [1]
We found that global Small Ubiquitinlike MOdifier (SUMO)-1 and SUMO-2/3 conjugation, as well as Ubc9 protein levels, were increased in Ubc9 Neural stem cell (NSC) (Fig. 1C)
We performed global SUMO-1 immunoprecipitation (IP) (Fig. 1D) and protein pathway analysis (Fig. 1E) confirming that, beyond SUMOylation and ubiquitination, protein pathways related to cell signaling, cell metabolism, and cell cycle were prevalent in Ubc9 NSCs (Data S1)
Summary
In ischemic stroke a crisis in energy availability due to the sudden reduction of oxygen and glucose leads to the depletion of cellular energy stores, aberrant neurotransmitter release, and intense cytotoxic/inflammatory responses [1]. ⁎ Corresponding author at: Department of Clinical Neurosciences, University of Cambridge, UK. Accounts for the continuing failure of clinical approaches targeting single pathogenic mechanisms. The successful translation of such promising cell-based approaches remains elusive, in part due to the fact that grafted NSCs often die in the hostile ischemic/postischemic microenvironment. Neural stem cell (NSC)-based therapies hold great promise for treating diseases of the central nervous system (CNS). Methods: we sought to engineer NSCs in an effort to increase graft survival within ischemic brain lesions via upregulation of global SUMOylation, a post-translational modification critically involved in mediating tolerance to ischemia/reperfusion. Interpretation: Our work highlights a critical role for SUMOylation in NSC biology and identifies a biological pathway that can be targeted to increase the effectiveness of exogenous stem cell medicines in ischemic stroke.
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