Mechanisms of Action of Mesenchymal Stromal Cell- Based Therapies in Animal Models of Neonatal Hypoxia-Ischemia

It is already well established that MSC do not transdifferentiate into functional neural cells in vivo (Abraham and Verfaillie 2012; Lin et al. 2015). Instead of replacing lost cells, MSC seem to exert their therapeutic effects through paracrine and contact- dependent signaling.

Zhou and coworkers (Zhou et al. 2015), for example, identified IL-8 as key player in the paracrine action of human umbilical cord-derived MSC in a rodent model of HIE. Silencing of IL-8 gene expression in MSC abolished the beneficial cognitive effects of a single intracerebroventricular injection of MSC. In addition, another study from the same group showed that rat BM-MSC exerted their therapeutic effects on cognition through the secretion of IL-6 and that this cytokine was involved in the protection of astrocytes in an in vitro model of oxygen/glucose deprivation (Gu et al. 2016).

The paracrine action of MSC is also supported by studies on the composition and biological activity of the conditioned medium of cultured MSC. IL-6, IL-8, vascular endothelial growth factor (VEGF) and the chemokine CCL2 are some of the factors most commonly found in the secretome of non-stimulated MSC (Ranganath et al. 2012). Moreover, the secretome can be modified by genetic manipulation (van Velthoven et al. 2014) or by changes in culture conditions (Ranganath et al. 2012). For instance, a recent study showed that the intranasal delivery of MSC genetically engineered to secrete brain-derived neurotrophic factor (BDNF) improved the motor function, decreased lesion volume and induced cell proliferation in the ischemic hemisphere, whereas the treatment with MSC modified to secrete epidermal growth factor-like 7 (EGFL7) only improved the motor function after HIE (van Velthoven et al. 2014).

The neuroprotective action of MSC-released factors was further demonstrated by Wei et al. (Wei et al. 2009), who treated neonatal rats with an intravenous injection of the conditioned medium of AT-MSC either 1 h before or 24 h after the hypoxic-i schemic insult. Both treatment protocols were effective in reducing brain tissue loss and preventing the development of long-term spatial learning deficits. Insulin-like growth factor-1 (IGF-1) and BDNF were partially responsible for the neuroprotective effects of the prophylactic administration of conditioned medium. These findings were corroborated by in vitro experiments showing that the conditioned medium protected cerebellar granular neurons against serum and K+ deprivation-induced cell death, as well as against glutamate excitotoxicity.

Taken together, these studies indicate that it may not be possible to identify a single factor that could explain the multiple actions of MSC. Future studies are necessary to compare the efficacy of MSC versus MSC-conditioned medium in animal models of HIE. A possible advantage of the cell therapy is the fact that MSC adapt their secretome in response to changes in the environment. For instance, the co-culture of MSC with brain extracts from hypoxic-ischemic animals increased the mRNA expression of BDNF and nerve growth factor (NGF) by MSC (Donega et al. 2014b). Therefore, MSC could act as a “site-regulated drugstore”, as suggested by Caplan and Correa (Caplan and Correa 2011). On the other hand, the administration of cells is not devoid of potential risks (Boltze et al. 2015) and the composition of the conditioned medium can be modulated by different types of stimuli.

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