New research explores the dynamic interplay of TGF-β and BMP signalling pathways in liver injury and repair, providing exciting therapeutic potential for acute and chronic liver treatment.
A new study, published in Science Signalling, investigated transforming growth factor β (TGF-β) and bone morphogenetic proteins (BMP) signalling in acetaminophen (APAP) intoxicated mice as a model for liver injury. Conducted by the Biomedical Research Foundation of the Academy of Athens, the findings have furthered understanding of the relationship between the TGF-β super family signalling pathways, and liver repair and regeneration.
“The study highlighted the complexity of the interplay between the two signalling systems,” the authors reported.
TGF-β and BMP signalling
TGF-β and BMP are cytokines of the TGF-β super family. Their pleiotropic functions involve wound healing, repair, maintenance and angiogenesis.
Previous studies suggested that TGF-β can impair liver regeneration in acetaminophen poisoning, which is a leading cause of liver failure in the Western world.
In this study, TFG-β and BMP double-reporter mice were treated with APAP to induce liver injury. Immunostaining revealed intense TGF- β and BMP activity in the zones distinguishing the borders between healthy and damaged hepatic tissue.
Transmission electron microscopy (TEM) confirmed the accompaniment of accumulated autophagosomes in these TGF- β and BMP positive regions. Using transcriptomic analysis, the authors identified TRP53INP2, an autophagy initiation factor that was upregulated upon TGF- β and BMP stimulation.
Inhibiting TGF-β superfamily signalling
In this study, Smad7, a negative regulator of both TGF-β and BMP signalling, was utilised to inhibit their effects. Smad7, was ectopically expressed in mouse livers before APAP administration. The results showed exacerbated centrilobular necrosis and supressed autophagic activity soon after APAP treatment.
“This was most likely due to obstruction of cargo protein recycling at an early stage of autophagosome formation,” the authors noted.
However, 4 days after APAP administration, Smad7 overexpression led to accelerated healing, as demonstrated by almost complete tissue restoration. This agreed with previous findings.
The authors reported, “Despite the agreement of accelerated tissue restoration, the previous studies did not mention the enhancement of histopathology and autophagic suppression by TGF- β inhibition observed in our study.”
The authors proposed that animal age, sex or genetic background might be responsible for this discrepancy between studies.
Overall, this inhibition of TFG-β superfamily signalling revealed contradictory results to previous studies shown by the initial aggravation of APAP-induced liver pathology in Smad7, expressing mice.
The authors explained, “Although the TGF-β and BMP signalling pathways cooperate in promoting autophagy, their interplay appears to be more complex.”
Nevertheless, the study crucially highlights the interconnectivity of TGF-β superfamily signalling systems. The identification of these molecules and their influence on liver regeneration could inform future research into therapies for acute and chronic liver conditions.
Written by Harry Yuen, Science Writer Intern
Image Credit: Canva