The pro-survival effects of milk-derived extracellular vesicles in response to perinatal stress: Regulation of the heat shock response

Abstract

Milk-derived extracellular vesicles (MEVs) are lipid-coated nanovesicles found in mammalian milk that survive intestinal degradation and cross complex biological barriers, including the bloodbrain barrier. MEVs have known cytoprotective and anti-inflammatory activity in peripheral organs, however, their biological functions remain unknown in the central nervous system. In this thesis, I investigated whether MEVs promote pro-survival responses by activating the heat shock response (HSR) in vitro (chapter 2) and in vivo (chapter 3). The HSR is a principal pro-survival mechanism responsible for refolding or degrading misfolded protein aggregates through the action of molecular heat shock protein (HSP) chaperones. Specifically, I investigated the interaction between MEVs and the HSR in immortalized human microglia clone 3 (HMC3) cells exposed to an acute stress (interferon-gamma), as well as in neonatal rats exposed to chronic stress (perinatal high-fat diet (mHFD) exposure). I found that MEVs promote the activation and maintenance of the HSR, specifically by upregulating the HSF1 transcription factor and by downregulating the negative regulators, Hsp70 and Hsp90. Interestingly, corresponding results were found across immortalized microglia and the prefrontal cortex of neonates. Collectively, I demonstrate that MEVs promote pro-survival in the context of alleviating neuroinflammation by activating HSF1-mediated pro-survival, and potentially prolonging HSR activity. The results presented here provide novel insights on cellular interactions between MEVs and the HSR.