Stem Cells Dev. 2017 Jan 19. doi: 10.1089/scd.2016.0268. [Epub ahead of print]

Strategies to enhance implantation and survival of stem cells after their injection in ischemic neural tissue.

Sandvig I¹, Gadjanski I², Vlaski M^3,4, Buzanska L⁵, Loncaric D^6,7, Sarnowska A^8,9, Rodriguez L^10,11, Sandvig A^12,13, Ivanovic Z^14,15.

Abstract

High post-transplantation cell mortality is the main limitation of various approaches aimed to improve regeneration of injured neural tissue by injection of neural stem cells (NSCs) and mesenchymal stromal cells (MStroCs) in and/or around the lesion. Therefore, it is of paramount importance to identify efficient ways to increase cell transplant viability. We have previously proposed the "evolutionary stem cell paradigm", which explains the association between stem cell anaerobic/microaerophilic metabolic set-up and stem cell self-renewal and inhibition of differentiation. Applying these principles, we have identified the main critical point in the collection and preparation of these cells for experimental therapy: exposure of the cells to atmospheric O2 i.e. to oxygen concentrations that are several times higher than the physiologically relevant ones. In this way, the primitive anaerobic cells become either inactivated or adapted, through commitment and differentiation, to highly aerobic conditions (20-21% O2 in atmospheric air). This inadvertently compromises the cells' survival once transplanted into normal tissue, especially in the hypoxic/anoxic/ischemic environment, which is typical of CNS lesions. In addition to the findings suggesting stem cells can shift to glycolysis and can proliferate in anoxia, recent studies also propose that stem cells may be able to proliferate in completely anaerobic or ischemic conditions by relying on anaerobic mitochondrial respiration. In this systematic review we propose strategies to enhance survival of NSCs and MStroCs implanted in hypoxic/ischemic neural tissue by harnessing their anaerobic nature and maintaining as well as enhancing their anaerobic properties via appropriate ex vivo conditioning.