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

Stavropoulos, A.; Divolis, G.; Manioudaki, M.; Gavriil, A.; Kloukina, I.; Perrea, D. N.; Sountoulidis, A.; Ford, E.; Doulou, A.; Apostolidou, A.; Katsantoni, E.; Ritvos, O.; Germanidis, G.; Xilouri, M.; Sideras, P.

doi:10.1101/2021.07.23.453185

bioRxiv · 10.1101/2021.07.23.453185

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

Stavropoulos, A.·Divolis, G.·Manioudaki, M.·Gavriil, A.·Kloukina, I.·Perrea, D. N.·Sountoulidis, A.·Ford, E.·Doulou, A.·Apostolidou, A.·Katsantoni, E.·Ritvos, O.·Germanidis, G.·Xilouri, M.·Sideras, P.

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Abstract

Transforming Growth Factor-{beta}s (TGF{beta}s)/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 TGF{beta}/Activin and BMP branches in health and disease is still not fully understood. To address this, TGF{beta}/BMP Smad- responsive double transgenic reporter mice were generated and utilized to map patterns of TGF{beta}- and/or BMP-pathway activation during acetaminophen- induced liver injury. TGF{beta} signaling was blocked either pharmacologically or by Smad7 over-expression and the transcriptomes of canonical TGF{beta}- and/or BMP4-treated hepatospheres and Smad7-treated livers were analyzed to highlight TGF{beta}-superfamily-regulated pathways and processes. Acetaminophen administration led to dynamically evolving, stage- and context-specific, patterns of hepatic TGF{beta}/Activin and BMP-reporter expression. TGF{beta}-superfamily signaling was activated in an autophagy prone zone at the borders between healthy and injured tissue. Inhibition of TGF{beta}-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 TGF{beta}1- and BMP4-regulated process and recognized Trp53inp2 as the top TGF{beta}-superfamily-regulated autophagy-related gene. Collectively, these findings implicate the coordinated activation of both canonical TGF{beta}-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.

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Stavropoulos, A., Divolis, G., Manioudaki, M., Gavriil, A., Kloukina, I., Perrea, D. N., Sountoulidis, A., Ford, E., Doulou, A., Apostolidou, A., Katsantoni, E., Ritvos, O., Germanidis, G., Xilouri, M., Sideras, P.. 2021-07-23. Coordinated activation of both TGFβ and BMP canonical pathways regulates autophagy and tissue regeneration in acetaminophen induced liver injury. https://doi.org/10.1101/2021.07.23.453185

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