Redox experimental medicine and liver regeneration

Abstract

The liver is characterized by unique regenerative properties to restore its mass and function after a partial loss. Hepatic regeneration arises after resection or following acute and chronic injuries. Resection and acute liver damage normally induce a regenerative process characterized by phenotypic fidelity, in which each cell type promotes its own replication and replacement. This process fails in chronic liver damage, where trans-differentiation of parenchymal cells or activation of facultative progenitors occurs. Both liver resection and acute/chronic damages alter redox homeostasis, as a consequence of blood flow changes, hypoxia, metabolism modification, and activation of inflammatory response. Even though formerly described as ‘oxidative stress’, altered redox homeostasis leads to the fine regulation of several pathways involved in liver regeneration, including the proliferation of parenchymal cells, trans-differentiation, and activation of facultative progenitors. Several redox-dependent transcription factors and pathways implicated in the regenerative process of the liver were described, but pre-clinical experiments using different antioxidants were not fully conclusive. Even though accurate study designs to define appropriate dosages, treatment duration, and routes of administration are required, modulation of redox-dependent molecular pathways to enhance liver regeneration is even more intriguing. Preliminary studies focused on the identification of these targets will pave the way for viable therapies to be tested in clinical trials.

Redox-Dependent Modulation of Human Liver Progenitor Cell Line Fate

“…Stem cells rely on their capacity to maintain pluripotency, self-renew, or activate/differentiate to promote regeneration on intricate signals in their niches. Characterized by special regenerative properties, the liver is able to respond to different stimuli, activating several pathways for mass restoration: indeed, acute organ loss induces hepatocellular proliferation characterized by phenotypic fidelity (canonical pathway), while chronic hepatic injury may activate the trans-differentiation of parenchymal cells or activation of facultative progenitors (alternative pathways) [1,2]. In particular, this latter regenerative mechanism involves a bipotent cell line located in the smallest branches of the ductular tree (regenerative niche), capable of differentiating toward hepatocyte or biliary cell lineages [3][4][5][6].…”

Redox Experimental Medicine: Linking redox research to human health and disease

“…The inaugural issue of Redox Experimental Medicine consists of a number of invited review papers focusing on the redox aspects of a large variety of human pathological disorders, associated with oxidative stress, like the involvement of oxidant species in the early attempt of the organism to counteract a sepsis (Beltran-Garcia et al 2022), in the dysfunction of endothelial nitric oxide synthase occurring in vascular diseases (Negre-Salvayre et al 2022), in liver regeneration (Bellanti et al 2022), in the complex inflammatory reactions promoting the progression of nonalcoholic fatty liver disease (Sutti and Albano 2022) or the derangement of the microbiota-gut-brain axis (Poli et al 2022). With regard to diabetes mellitus, nutritional supplementation with redox bioactive compounds was proposed to prevent or ameliorate muscle loss (Lee et al 2022) and the improvement of mitochondrial function outlined as one of the primary targets of this syndrome's treatment (de Marañón et al 2022).…”