(526.16) Modulation of miR-21 can reprogram the TGF-β signaling pathway to alter HSC phenotype in vitro

Poster Board Number: D33
Introduction:

Ankita Srivastava (Thomas Jefferson University), Austin Parrish (Thomas Jefferson University), Jan Hoek (Thomas Jefferson University), Rajanikanth Vadigepalli (Thomas Jefferson University)

microRNAs are small non-coding RNAs capable of modulating gene expression through post-transcriptional modification affecting fundamental regulatory mechanisms to control cell function and play a significant role in the transition between cell states. Previous studies have demonstrated the differential expression of specific microRNAs in the context of disease states including alcoholic liver disease. Research from our group and others have identified several miRNAs as potential regulators of liver regeneration, such as miR-21, whose role in liver regeneration and liver disease is well-characterized, and several other miRNAs that show differential expression in response to altered miR-21 expression. Dysregulation of miR-21 expression has been implicated in altered hepatic stellate cell (HSC) activation. A potential mechanism for ethanol-mediated impairment of liver regeneration is due to TGF-β/SMAD/SMURF signaling in activated HSCs. In this study, we have characterized the HSCs response to miR-21 dysregulation followed by TGF-β stimulation using human hepatic stellate cell line LX2. We manipulated miR-21 activity using locked nucleic acid oligos to either inhibit or mimic miR-21. Our findings show that inhibition of miR-21 activity followed by TGF-β stimulation leads to the altered expression of components of the TGF-β signaling pathway that in effect attenuated the downstream response to TGF-β. By contrast, enhancing miR-21 activity using a mimic amplified response to TGF-β signal. This reprogramming of the TGF-β  pathway by exogenous alterations in miR-21 activity was reflected in the modulation of HSC activation signature and migration phenotype. Taken together, our results show that changes in miR-21 activity rewires the TGF-β  signaling network with consequences on HSC phenotype in vitro.

Funding: National Institute of Alcoholism and Alcohol Abuse: R01 AA018873; National Institute of Biomedical Imaging and Bioengineering: U01 EB023224.