Prolonged XXXX induces monocarboxylate transporter-4 expression in mesenchymal stem cells resulting in a secretome that is deleterious to cardiovascular repair.

@entity71808 @entity19 @entity26 @entity519 @entity880 @entity3612 @entity3338
MSCs encounter extended @entity519 in the wound microenvironment yet little is known about their adaptability to this prolonged @entity519 milieu. In this study, we evaluated the cellular and molecular response of MSCs in extended @entity519 (1% @entity3612 ) versus normoxia (20% @entity3612 ) culture. Prolonged @entity519 induced a switch toward anaerobic glycolysis transcriptome and a dramatic increase in the transcript and protein levels of @entity3338 transporter-4 ( @entity71808 ) in MSCs. To clarify the impact of @entity71808 upregulation on MSC biology, we generated MSCs which stably overexpressed @entity71808 ( @entity71808 ) at levels similar to wild-type MSCs following prolonged @entity519 culture. Consistent with its role to efflux @entity880 to maintain intracellular pH, @entity71808 -MSCs demonstrated reduced intracellular @entity880 . To explore the in vivo significance of @entity71808 upregulation in MSC therapy, @entity19 were injected intramuscularly following MI with control (GFP)-MSCs, @entity71808 -MSCs, or MSCs in which @entity71808 expression was stably silenced (KDMCT4-MSCs). Overexpression of @entity71808 worsened cardiac remodeling and cardiac function whereas silencing of @entity71808 significantly improved cardiac function. @entity71808 -overexpressing MSC secretome induced reactive @entity26 species-mediated cardiomyocyte but not fibroblast apoptosis in vitro and in vivo; @entity880 alone recapitulated the effects of the @entity71808 -MSC secretome. Our findings suggest that @entity880 extruded by @entity71808 -overexpressing MSCs preferentially induced cell death in cardiomyocytes but not in fibroblasts, leading ultimately to a decline in cardiac function and increased scar size. A better understanding of stem cells response to prolonged @entity519 stress and the resultant stem cell-myocyte/fibroblast cross-talk is necessary to optimize MSC-based therapy for cardiac regeneration.
