miR-15a reprograms activated hepatic stellate cells back toward quiescence

Cell reprogramming enables dedifferentiation to generate induced pluripotent stem cells or transdifferentiation to produce desired terminally differentiated cell types. However, the concept of forced reprogramming has not been extended to converting the activation status of specialized cell types such as hepatic stellate cell (HSC) which, once activated, plays a central role in promoting liver fibrosis. We identified miR-15a as a key driver to reprogram activated HSC back toward quiescence, partly by directly targeting Wisp1, to generate what we designate as induced quiescent-like HSC (iqHSC). iqHSCs had a morphologic, transcriptional, and functional phenotype similar to that of truly quiescent HSCs. Finally, performing cell therapy with iqHSCs attenuated hepatic inflammation and fibrosis in mouse models of liver injury induced by toxin, biliary obstruction, or diet. We performed RNA sequencing of hepatic stellate cells in various activation states to predict a set of genes that have a higher likelihood of being targeted by miR-15a.