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Neckermann, L.* ; Erdösi, P.* ; Zhang, L. ; Assum, I. ; Dropmann, A.* ; Alaoua, S.* ; Büttner, M. ; Lin, T.* ; Gerstner, M.* ; Ebert, M.P.* ; Bantel, H.* ; Dooley, S.* ; Kluth, A.* ; Menden, M.P. ; Martinez Jimenez, C.P. ; Hammad, S.*

Preclinical evaluation of human ABCB5+ skin-derived stem cells reveals regenerative mechanisms and prognostic markers in a novel ACLF mouse model.

Z. Gastroenterol. 63, e452 - e452 (2025)

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Acute-on-chronic liver failure (ACLF) is a life-threatening condition in chronic liver disease (CLD) patients, often triggered by a precipitating event such as drug or viral infection. High short-term mortality (>30% within 28 days) and the lack of predictive biomarkers or effective therapies demand new preclinical approaches. We established a novel in vivo model using aged Abcb4/Mdr2-/- mice (60–65 weeks), which develop cholestatic CLD [1], in combination with a sublethal dose of hepatotoxic compound (CCl₄) to mimic ACLF. This model reproduces key ACLF features including acute decompensation on CLD background, multi-organ failure, and a critical 24-hour “golden window” predicting divergent outcomes: survival with massive hepatic necrosis and recovery, versus rapid death with minimal necrosis. Using a time-resolved transcriptomic and proteomic profiling, we identified two distinct disease trajectories: a recovery-associated metabolic signature (e.g. Acot1, Hmgcs1, G6pc), and an injury-driven inflammatory signature (e.g. Fgg, Itgam, Cd63). These molecular patterns were conserved in human ACLF datasets and associated with disease severity. ROC analysis revealed nine candidate biomarkers (e.g. Abhd4, Cd14, Slc38a2) for early prognosis. Single-nucleus RNA sequencing uncovered distinct cell populations, including hepatocytes and immune cells with enriched pro-apoptotic and ROS pathways in poor-outcome mice. To address the therapeutic impact, we tested human ABCB5⁺skin-derived mesenchymal stem cells and their macrophage-stimulated secretome. These stem cells enhanced hepatocyte function in vitro (e.g. albumin production), and, applied intravenously, are being evaluated in vivo for their impact on tissue injury, inflammation, regeneration, and survival. Preliminary results indicate a shift in clinical outcome in mice, with an increased survival in the ABCB5⁺ stem cell-treated group, suggesting a potential reduction in the proportion of poor-prognosis cases.

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