Characterization of Pro-Fibrotic Signaling Pathways using Human Hepatic Organoids

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.25.538102v1?rss=1 Authors: Guan, Y., Fang, Z., Hu, A., Roberts, S., Johansson, P. K., Heilshorn, S. C., Enejder, A., Peltz, G. Abstract: Due to the limitations of available in vitro systems and animal models, we lack a detailed understanding of the pathogenetic mechanisms and have minimal treatment options for liver fibrosis. To overcome this barrier, we engineered a live cell imaging system that identifies collagen producing cells in a human multi-lineage hepatic organoid. This system was adapted for use as a microwell-based platform (i.e., microHOs) where exposure to PDGF or TGFb1 induced the formation of thick collagen fibers. Transcriptomic analysis revealed that TGFb1 exposure converted mesenchymal cells into myofibroblast-like cells with a significantly altered pattern of production of proteases and anti-proteases, which contribute to the development of liver fibrosis. When pro-fibrotic intracellular signaling pathways were examined using pharmacological probes, the anti-fibrotic effect of receptor-specific tyrosine kinase inhibitors was limited to the fibrosis induced by the corresponding growth factor, which indicates that their antifibrotic efficacy would be limited to fibrotic diseases that were solely mediated by that growth factor. In contrast, GSK3b or p38 MAPK inhibitors could prevent TGFb1- or PDGF-induced fibrosis in microHOs because they block intracellular signaling pathways that are commonly utilized by the TGFb1 and PDGF receptors. Hence, these studies identified GSK3b and p38 MAPK inhibitors as potential new broad-spectrum therapies for liver fibrosis, and it is likely that other new therapies could subsequently be identified using this microHO system. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC