The Role of Concomitant Nrf2 Targeting and Stem Cell Therapy in Cerebrovascular Disease

Abstract

Despite the reality that a death from cerebrovascular accident occurs every 3.5 min in the United States, there are few therapeutic options which are typically limited to a narrow window of opportunity in time for damage mitigation and recovery. Novel therapies have targeted pathological processes secondary to the initial insult, such as oxidative damage and peripheral inflammation. One of the greatest challenges to therapy is the frequently permanent damage within the CNS, attributed to a lack of sufficient neurogenesis. Thus, recent use of cell-based therapies for stroke have shown promising results. Unfortunately, stroke-induced inflammatory and oxidative damage limit the therapeutic potential of these stem cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been implicated in endogenous antioxidant and anti-inflammatory activity, thus presenting an attractive target for novel therapeutics to enhance stem cell therapy and promote neurogenesis. This review assesses the current literature on the concomitant use of stem cell therapy and Nrf2 targeting via pharmaceutical and natural agents, highlighting the need to elucidate both upstream and downstream pathways in optimizing Nrf2 treatments in the setting of cerebrovascular disease.

Attenuation of amyotrophic lateral sclerosis via stem cell and extracellular vesicle therapy: An updated review

“… 42 Nrf2 is an important driver of a battery of antioxidant genes, also relevant in cerebral ischemia. 43 In fact, miRNA‐466m‐5p and miRNA‐466i‐3p mimics prompted nuclear translocation of Nrf2 in SOD1 G93A astrocytes; additionally, miRNA‐466q and miRNA‐467f mimics were again found to be relevant, by downregulating Mapk11. In human astrocytes, miRNA‐29b‐3p mimic was found to upregulate the antioxidant activity of NAD(P)H quinone dehydrogenase 1 (NQO1).…”

“…SOD1 G93A astrocytes' pathological phenotype and neuroinflammation were ameliorated with EV therapy, and human astrocytes increased nuclear factor‐erythroid 2‐related factor‐2 (Nrf2) and reduced reactive oxygen species (ROS) expression 42 . Nrf2 is an important driver of a battery of antioxidant genes, also relevant in cerebral ischemia 43 . In fact, miRNA‐466m‐5p and miRNA‐466i‐3p mimics prompted nuclear translocation of Nrf2 in SOD1 G93A astrocytes; additionally, miRNA‐466q and miRNA‐467f mimics were again found to be relevant, by downregulating Mapk11.…”

Stem Cells Attenuate the Inflammation Crosstalk Between Ischemic Stroke and Multiple Sclerosis: A Review

“…The notion of priming MSCs has been demonstrated to enhance their therapeutic potential against stroke damage 53 . There is also a plethora of evidence supporting amplification of the Nrf2/HO-1 pathway to ameliorate stroke damage 54 .…”

“…The anti-oxidant response promotes SC survival and reduces neuronal ischemic injury. Nrf2, a transcription factor involved in the anti-oxidant response, is strongly associated with endogenous NSC survival, and thus drug-based therapies focused on the Nrf2 pathway may enhance the effects of exogenous SC transplantation 54 .…”

Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke

“…These effects are also transferable to animals, reducing infarct volumes in mice models [ 38 ]. Nrf2 plays a well-established role in neuroprotection following stroke [ 39 ], and its amplification with HDAC inhibitors may be beneficial in clinical settings. With a better understanding of histone modifications and their role in stroke-induced neuroinflammation, pharmaceuticals or cell-based therapies may be developed to reduce this mechanism of secondary cell death following stroke.…”