Abstract
Hibernating 13-lined ground squirrels (Ictidomys tridecemlineatus; TLGS) rank among the most brain hypoperfusion-tolerant mammals known. Herein we provide some evidence of cycling between an epithelial phenotype and a hybrid epithelial/mesenchymal (E/M) phenotype (partial EMT) within the brains of TLGS during each bout of hibernation torpor. During hibernation torpor, expression of the epithelial marker E-cadherin (E-CDH) was reduced, while expression of the well-known mesenchymal markers vimentin and Sox2 were increased. P-cadherin (P-CDH), which has recently been proposed as a marker of intermediate/partial EMT, also increased during torpor, suggesting that a partial EMT may be taking place during hibernation torpor. Members of the miR-200 family and miR-182 cluster and Akt isoforms (Akt1, Akt2), well-known EMT regulators, were also differentially regulated in the TLGS brain during hibernation bouts. Using SHSY5Y cells, we also demonstrate that the Akt1/Akt2 ratio determined the expression levels of miR-200/miR-182 miRNA family members, and that these miRNAs controlled the expression of EMT-related proteins. Accordingly, we propose that such cell state transitions (EMT/MET) may be one of the mechanisms underlying the extraordinary ischemic tolerance of the TLGS brain during hibernation bouts; hibernator brain cells appear to enter reversible states that confer the stress survival characteristics of cancer cells without the risk of neoplastic transformation.
Highlights
In the quest to discover effective cytoprotective agent capable of mitigating the damage that occurs during/after an ischemic stroke, our lab has focused on broad, plurifunctional targets that have been shown to maintain homeostasis in hibernation, a state of natural tolerance to brain ischemia
Of note, altered microRNA expression is frequently seen in human cancers (Calin and Croce, 2006; Croce, 2009) and we have previously shown that the miRNA 183-96182 cluster and miR-200 family members are consistently down-regulated during hibernation torpor
Expression of miR-200 family and miR-182 cluster miRNAs was regulated in a similar manner during the hibernation bout
Summary
In the quest to discover effective cytoprotective agent capable of mitigating the damage that occurs during/after an ischemic stroke, our lab has focused on broad, plurifunctional targets that have been shown to maintain homeostasis in hibernation, a state of natural tolerance to brain ischemia. In 13-lined ground squirrels (Ictidomys tridecemlineatus; TLGS), cerebral blood flow (CBF) declines to roughly ∼10% of baseline rate during hibernation torpor (Frerichs et al, 1994). Such hypoperfusion is equivalent to that which is present in the ‘‘ischemic core’’ of an ischemic stroke, a tissue zone regarded as clinically unsalvageable without the rapid restoration of CBF. Our group and others have shown that increased global SUMOylation is, a mechanism that provides protection against ischemia in both murine brains and myriad neuronal cell lines (Lee and Hallenbeck, 2013; Bernstock et al, 2018)
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