Modeling Fibrosis with MASH Patient Liver-Derived Organoids.

Metabolic dysfunction-associated steatohepatitis (MASH) can lead to liver fibrosis and cirrhosis ultimately leading to liver transplantation or death. Therapeutic options for MASH-associated fibrosis are limited in part because of the lack of good model systems. To address this challenge, we developed a 3D MASH liver fibrosis model by using organoids derived from MASH patient liver co-cultured with human liver-derived hepatic stellate cells (HSC) and human peripheral blood monocytes (MC). Spontaneous self-assembly resulted in fibrotic scar-like 3D structures with senescent parenchymal cells, proliferating collagen secreting myofibroblasts (MFB) and proinflammatory TREM2+ scar-associated macrophages (MP). Single cell RNA sequencing suggested high similarity with MASH patient liver fibrotic scars. Lipid nanoparticles (LNPs) formulated with anti-YAP1siRNA could specifically and efficiently knockdown YAP1 in the MFBs, resulting in MFB senescence, a desirable therapeutic goal. This MASH patient liver-derived fibrosis model opens novel avenues towards testing treatments for MASH-associated liver fibrosis with reduced adverse effects.