Coordinated activation of both TGFβ and BMP canonical pathways regulates autophagy and tissue regeneration in acetaminophen induced liver injury

Abstract

AbstractTransforming Growth Factor-βs (TGFβs)/Activins and Bone Morphogenetic Proteins (BMPs) have been implicated in numerous aspects of hepatic pathophysiology. However, the way by which hepatocytes integrate and decode the interplay between the TGFβ/Activin and BMP branches in health and disease is still not fully understood. To address this, TGFβ/BMP Smad- responsive double transgenic reporter mice were generated and utilized to map patterns of TGFβ- and/or BMP-pathway activation during acetaminophen- induced liver injury. TGFβ signaling was blocked either pharmacologically or by Smad7 over-expression and the transcriptomes of canonical TGFβ- and/or BMP4-treated hepatospheres and Smad7-treated livers were analyzed to highlight TGFβ-superfamily-regulated pathways and processes. Acetaminophen administration led to dynamically evolving, stage- and context-specific, patterns of hepatic TGFβ/Activin and BMP-reporter expression. TGFβ-superfamily signaling was activated in an autophagy prone zone at the borders between healthy and injured tissue. Inhibition of TGFβ-superfamily signaling attenuated autophagy, exacerbated liver histopathology, and finally led to accelerated tissue-recovery. Hallmarks of this process were the paraptosis-like cell death and the attenuation of immune and reparatory cell responses. Transcriptomic analysis highlighted autophagy as a prominent TGFβ1- and BMP4-regulated process and recognized Trp53inp2 as the top TGFβ-superfamily-regulated autophagy-related gene. Collectively, these findings implicate the coordinated activation of both canonical TGFβ-superfamily signalling branches in balancing autophagic response and tissue-reparatory and -regenerative processes upon acetaminophen-induced hepatotoxicity, highlighting opportunities and putative risks associated with their targeting for treatment of hepatic diseases.