Exploring the memory of the extracellular matrix using MASH-derived decellularized scaffolds.

Abstract

Emerging evidence suggests that the extracellular matrix (ECM) possesses a "memory" that can influence cell physiology and recellularization outcomes. Understanding this memory is essential to allow the use of bioengineered organs derived from diseased ECM, offering a solution to the critical organ shortage. To address this, we investigated whether the memory of ECM derived from metabolic dysfunction-associated steatohepatitis (MASH) livers impacts disease establishment following transplantation. Partial orthotopic transplantation of decellularized MASH-derived ECM was performed in control and MASH recipients. Histological analysis confirmed complete recellularization; however, molecular and metabolomic analyses revealed that MASH ECM stimulated de novo lipogenesis and fibrogenesis, inducing impaired lipid oxidation and mitochondrial dysfunction, which contributed to disease progression by promoting altered lipid turnover and inflammatory signalling. In vitro analysis revealed that MASH-ECM disrupted calcium signalling and promoted the maintenance of a pathological phenotype. Although derived from diseased livers, human ECM can promote cell survival and permissiveness. In conclusion, diseased ECM memory impacts cell physiology, suggesting that the scaffold can drive disease progression independently of the cellular environment. Thus, further studies are needed to develop strategies capable of reversing the pathological memory associated with ECM to allow its use in liver transplantation.