Background & Aims: Fibrosis, a cardinal feature of a dysfunctional liver, significantly contributes to the ever-increasing mortality due to end-stage chronic liver diseases. The cross-talk, between hepatocytes and hepatic stellate cells, is suggested to play a key role in fibrosis progression. While ample efforts have been devoted to elucidate hepatic stellate cells' functions during liver fibrosis, the regulatory functions of hepatocytes remain elusive. Methods: Using an unbiased functional microRNA screening, we investigated the ability of hepatocytes to regulate fibrosis by fine-tuning gene expression via microRNA modulation. The in vivo functional analyses were performed by inhibiting microRNA in hepatocytes using adeno-associated virus in carbon-tetrachloride-and 3,5-di diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis. Results: We discovered that blocking microRNA-221-3p function in hepatocytes during chronic liver injury facilitates recovery of the liver and faster resolution of the deposited extracellular matrix. Further, we demonstrate that reduced secretion of CC motif chemokine ligand 2, due to post-transcriptional regulation of G protein alpha inhibiting activity polypeptide 2 by microRNA-221-3p, mitigates liver fibrosis. Page%5%of%44% % % Conclusions: Collectively, microRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis.

The organized array of smooth muscle cells (SMCs) and fibroblasts in the walls of visceral tubular organs arises by patterning and differentiation of mesenchymal progenitors surrounding the epithelial lumen. Here, we show that the TBX2 and TBX3 transcription factors have novel and required roles in regulating these processes in the murine ureter. Co-expression of TBX2 and TBX3 in the inner mesenchymal region of the developing ureter requires canonical WNT signaling. Loss of TBX2/TBX3 in this region disrupts activity of two crucial drivers of the SMC program, Foxf1 and BMP4 signaling, resulting in decreased SMC differentiation and increased extracellular matrix. Transcriptional profiling and chromatin immunoprecipitation experiments revealed that TBX2/TBX3 directly repress expression of the WNT antagonists Dkk2 and Shisa2, the BMP antagonist Bmper and the chemokine Cxcl12. These findings suggest that TBX2/TBX3 are effectors of canonical WNT signaling in the ureteric mesenchyme that promote SMC differentiation by maintaining BMP4 and WNT signaling in the inner region, while restricting CXCL12 signaling to the outer layer of fibroblast-fated mesenchyme.

All epithelial components of the inner ear, including sensory hair cells and innervating afferent neurons, arise by patterning and differentiation of epithelial progenitors residing in a simple sphere, the otocyst. Here, we identify the transcriptional repressors TBX2 and TBX3 as novel regulators of these processes in the mouse. Ablation of Tbx2 from the otocyst led to cochlear hypoplasia whereas loss of Tbx3 was associated with vestibular malformations. The loss of function of both genes (Tbx2/3cDKO) prevented inner ear morphogenesis at midgestation, resulting in indiscernible cochlear and vestibular structures at birth. Morphogenetic impairment occurred concommitantly with increased apoptosis in ventral and lateral regions of Tbx2/3cDKO otocysts around E10.5. Expression analyses revealed partly disturbed regionalisation, and a posterior-ventral expansion of the neurogenic domain in Tbx2/3cDKO otocysts at this stage. We provide evidence that repression of FGF signalling by TBX2 is important to restrict neurogenesis to the anterior-ventral otocyst and implicate another T-box factor, TBX1, as a critical mediator in this regulatory network.