SUMOylation promotes survival and integration of neural stem cell grafts in ischemic stroke

EBioMedicine. 2019 Apr;42:214-224. doi: 10.1016/j.ebiom.2019.03.035. Epub 2019 Mar 21.

Abstract

Background: Neural 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.

Methods: Herein, 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.

Findings: NSCs 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.

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. FUND: Intramural 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.

Keywords: Cell therapy; Cellular engineering; Ischemia/reperfusion; Neural stem cells (NSCs); Regenerative medicine; SUMOylation; Stroke; Ubc9.

MeSH terms

  • Animals
  • Biomarkers
  • Cell Cycle / genetics
  • Cell Survival* / genetics
  • Computational Biology / methods
  • Energy Metabolism
  • Gene Expression
  • Gene Expression Profiling
  • Glucose / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Neurogenesis / genetics
  • Neurons / cytology
  • Neurons / metabolism
  • Oxygen / metabolism
  • Signal Transduction
  • Stem Cell Transplantation
  • Stroke / etiology
  • Stroke / metabolism*
  • Sumoylation
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism

Substances

  • Biomarkers
  • Ubiquitin-Conjugating Enzymes
  • ubiquitin-conjugating enzyme UBC9
  • Glucose
  • Oxygen