UC Irvine

Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered one of the most pervasive liver disorders that can progress to more severe stages, causing irreversible damage to the liver. Given the limited treatment options for patients with MASLD, models that can recapitulate critical features of disease pathogenesis are needed for therapy evaluation. Here, a MASLD model was developed by first differentiating hepatocyte-like cells (HLC) from human induced pluripotent stem cells (hiPSCs) in both 2D and 3D, where hepatic aggregates (HA) exhibited enhanced functionality. HLCs exposed to free fatty acids (FFA) led to a steatotic phenotype and partial loss of hepatic function. Biochemical cues released from the MASLD model promoted the activation of the stromal cells, resulting in increased inflammatory cytokine secretion and deposition of extracellular matrix components. Secretome analysis identified MCP4 as the leading cytokine released by the MASLD model, and the treatment of MCP4 alone was able to activate the fibroblast. These findings suggest underlying paracrine signaling pathways from the hepatocytes to the surrounding stroma that trigger the progression of MASH and liver fibrosis. Collectively, the results showcase the utility of hiPSC derivatives in modeling liver disease, unveiling how heterotypic interactions can drive disease progression. Furthermore, biomaterials with various physical properties were applied to enhance hepatic maturation and functionality through tissue engineering, providing an enhanced platform for complex MASLD modeling.