Liver impairment by senescence is caused by hepatocyte reversal to a CD44high de-differentiation state

Loss of tissue homeostasis increases the risk of developing chronic diseases. To maintain integrity, cells in damaged areas can de-differentiate towards progenitors, which then expand, re-differentiate, and restore function. Factors secreted by senescent cells chronically impair tissue homeostasis, but it remains poorly understood how. Here, we show that senescent cells can induce plasticity of neighboring cells into a CD44 ^high state. In hepatocyte organoids and multicellular iPSC-derived 3D liver structures this results in an IL-1β, IL-6 and IKK-dependent loss of functional biomarkers, such as Albumin and Cyp3A4, and a blocks recovery from physical injury. Importantly, eliminating senescent cells with a compound resistant to liver enzymes and with potent liver uptake, CL04183, counters the CD44 ^high state and restores hepatocyte differentiation in vitro and in vivo. Thus, senescent cells are a culprit in liver homeostasis, by driving long-term, but reversible, de-differentiation of hepatocytes towards a CD44 ^high state.