Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor

Abstract

The liver is among the few organs having the ability to self-regenerate in response to a severe damage compromising its functionality. The Aryl hydrocarbon receptor (Ahr) is a transcription factor relevant for the detoxification of xenobiotics but also largely important for liver development and homeostasis. Hence, liver cell differentiation is developmentally modulated by Ahr through the controlled expression of pluripotency and stemness-inducing genes. Here, 2/3 partial hepatectomy (PH) was used as a clinically relevant approach to induce liver regeneration in Ahr-expressing (Ahr+/+) and Ahr-null (Ahr−/−) mice. Ahr expression and activity were early induced after 2/3 PH to be gradually downmodulated latter during regeneration. Ahr−/− mice triggered liver regeneration much faster than AhR+/+ animals, although both reached full regeneration at the latest times. At initial stages after PHx, earlier regenerating Ahr−/− livers had upregulation of cell proliferation markers and increased activation of signalling pathways related to stemness such as Hippo-YAP and Wnt/β-catenin, concomitantly with the induction of pro-inflammatory cytokines TNFa, IL6 and p65. These phenotypes, together with the improved metabolic adaptation of Ahr−/− mice after PHx and their induced sustained cell proliferation, could likely result from the expansion of undifferentiated stem cells residing in the liver expressing OCT4, SOX2, KLF4 and NANOG. We propose that Ahr needs to be induced early during regeneration to fine-tune liver regrowth to physiological values. Since Ahr deficiency did not result in liver overgrowth, its transient pharmacological inhibition could serve to improve liver regeneration in hepatectomized and transplanted patients and in those exposed to damaging liver toxins and carcinogens.

The aryl hydrocarbon receptor maintains antitumor activity of liver resident natural killer cells after partial hepatectomy in C57BL/6J mice

“…14,41,42 In addition, regeneration of the liver after PH improves in the absence of AhR. 43 The transient inhibition of AhR may improve liver regeneration in patients with liver resection and transplant. In this study, AhR had been involved in cell proliferation and the induction of inflammatory cytokines, tumor necrosis factor-alpha (TNFα), and interleukin (IL)-6 in the early phase after PH.…”

“…Furthermore, recent studies have demonstrated compelling data to support the vital role of AhR signaling in innate immunity 14,41,42 . In addition, regeneration of the liver after PH improves in the absence of AhR 43 . The transient inhibition of AhR may improve liver regeneration in patients with liver resection and transplant.…”

“…In this study, AhR had been involved in cell proliferation and the induction of inflammatory cytokines, tumor necrosis factor-alpha (TNFα), and interleukin (IL)-6 in the early phase after PH. 43 Liver regeneration after PH is regulated by various immune cells through direct interaction with hepatocytes or indirectly by releasing inflammatory cytokines. 44 NK and NKT cells have a high potential to TNF-α and IL-6 and may promote normal regenerative responses in the liver.…”

“…The transient inhibition of AhR may improve liver regeneration in patients with liver resection and transplant. In this study, AhR had been involved in cell proliferation and the induction of inflammatory cytokines, tumor necrosis factor‐alpha (TNF‐α), and interleukin (IL)‐6 in the early phase after PH 43 . Liver regeneration after PH is regulated by various immune cells through direct interaction with hepatocytes or indirectly by releasing inflammatory cytokines 44 .…”

From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms

“…This fact is supported by previous studies that show that AHR prevents mitotic progression and induces differentiation, as well as preventing pluripotency in different cell types [ 28 , 30 , 126 , 127 , 128 ]. Moreover, several groups of genes involved in cell differentiation and development are regulated directly by AHR in the absence of an exogenous ligand [ 129 , 130 ].…”