Altered Properties of Bone Marrow-Derived Mesenchymal Stem Cells Exposed to Serum from Patients with Acute-On-Chronic...

Acute-on-chronic liver failure (ACLF) is a high-mortality syndrome characterized by acute decompensation of liver function. Oxidative stress exerts a pivotal regulatory role in ACLF. Mesenchymal stem cell (MSC)-based therapy is a promising strategy for ACLF, with well-documented safety and efficacy profiles. However, long-term exposure to an oxidative microenvironment can impair MSC regenerative capacity and trigger senescence. Thus, elucidating how the pathological ACLF serum microenvironment affects the biological characteristics of MSCs is important for advancing MSC-based therapeutic strategies. This study investigated the biological alterations of MSCs exposed to ACLF patient serum. We demonstrated that ACLF serum markedly impaired MSC morphology, proliferation, and migration, induced energy metabolism dysfunction, and promoted senescence in vitro. In addition, the levels of advanced oxidation protein products (AOPPs), which are oxidative stress markers, were significantly elevated in the serum of ACLF patients, and this increase was positively correlated with the extent of MSCs senescence. Furthermore, we discovered that ACLF patient serum could lead to elevated intracellular reactive oxygen species (ROS) levels, which in turn drove MSCs senescence. Taken together, these findings suggested that the oxidative microenvironment of ACLF patient serum could alter the functional properties of MSCs and accelerate MSCs senescence through the induction of excessive ROS production. These results help clarify the pivotal role of AOPPs in mediating MSCs senescence and functional impairment, and highlight that monitoring serum AOPPs levels may be a promising biomarker for determining the optimal time window for MSCs transplantation in patients with ACLF.