Strategies to Enhance Implantation and Survival of Stem Cells After Their Injection in Ischemic Neural Tissue

Abstract

High post-transplantation cell mortality is the main limitation of various approaches that are aimed at improving regeneration of injured neural tissue by an 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 O, that is, 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% O in atmospheric air). This inadvertently compromises the cells' survival once they are transplanted into normal tissue, especially in the hypoxic/anoxic/ischemic environment, which is typical of central nervous system (CNS) lesions. In addition to the findings suggesting that 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 the survival of NSCs and MStroCs that are 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.

Cellularizing hydrogel-based scaffolds to repair bone tissue: How to create a physiologically relevant micro-environment?

“…244 Pre-conditioning of MSCs by growing them in hypoxic conditions has shown some benefits on MSC survival and on some of their physiological properties; 245 but to our knowledge, these strategies have not been explored in the context of in vivo bone formation or bone defect repair. An alternative strategy to help cell surviving the in vivo hypoxic environment is to provide them with an extra oxygen store using synthetic oxygen carriers, which can slowly release oxygen transiently until vascularization is restored.…”

Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy

“…Ischemic or hypoxic preconditioning treatments have been shown to promote tolerance and regenerative properties of transplanted stem cells, increasing their resistance to low substrates and oxygen availability in degenerating tissue via adaptive responses such as the upregulation of anti-apoptotic genes (Bcl-2, HIF-1) and reduction in caspase-3 activity (Table 1) [50]. Additionally, NSCs have been hypothesized to be physiologically predisposed to anaerobic/microaerophilic metabolic patterns, which enhance self-renewal and inhibit differentiation [52]. Therefore, exposure of the cells to highly aerobic conditions, such as atmospheric oxygen, before transplantation might unwillingly compromise their survival once injected into neural tissues, especially the hypoxic/anoxic environment typical of neurodegenerative diseases [52].…”

Neural Stem Cell Plasticity: Advantages in Therapy for the Injured Central Nervous System

“…While lipid metabolism maintains proliferation and neurogenesis (structural and energy support), glycolysis regulates NSCs development and differentiation (Knobloch et al, 2013). The metabolic activity strongly depends on oxidative saturation because in mammalian CNS oxygen regulates the growth and differentiation state of stem cells (De Filippis and Delia, 2011; Ivanovic and Vlaski-Lafarge, 2016; Sandvig et al, 2017). Dividing progenitor cells depend more on glycolysis, whereas differentiated progeny relies on energetically efficient oxidative phosphorylation occurring at low oxygen concentration.…”

“…For instance, in vitro preconditioning with low oxygen tension might enhance NSC survival as it mimics the oxygen supply normally found in brain tissues (Hawkins et al, 2013; Sandvig et al, 2017). Nonetheless, it is this same plasticity that could threaten their therapeutic capacity, because the manipulation of cells themselves or of the trophic microenvironment, might induce unwanted side-effects, such as senescence from over-stimulation.…”