Liver Injury and Regeneration: Current Understanding, New Approaches, and Future Perspectives

Abstract

The liver is a complex organ with the ability to regenerate itself in response to injury. However, several factors can contribute to liver damage beyond repair. Liver injury can be caused by viral infections, alcoholic liver disease, non-alcoholic steatohepatitis, and drug-induced liver injury. Understanding the cellular and molecular mechanisms involved in liver injury and regeneration is critical to developing effective therapies for liver diseases. Liver regeneration is a complex process that involves the interplay of various signaling pathways, cell types, and extracellular matrix components. The activation of quiescent hepatocytes that proliferate and restore the liver mass by upregulating genes involved in cell-cycle progression, DNA repair, and mitochondrial function; the proliferation and differentiation of progenitor cells, also known as oval cells, into hepatocytes that contribute to liver regeneration; and the recruitment of immune cells to release cytokines and angiogenic factors that promote or inhibit cell proliferation are some examples of the regenerative processes. Recent advances in the fields of gene editing, tissue engineering, stem cell differentiation, small interfering RNA-based therapies, and single-cell transcriptomics have paved a roadmap for future research into liver regeneration as well as for the identification of previously unknown cell types and gene expression patterns. In summary, liver injury and regeneration is a complex and dynamic process. A better understanding of the cellular and molecular mechanisms driving this phenomenon could lead to the development of new therapies for liver diseases and improve patient outcomes.

Regenerative human liver organoids (HLOs) in a pillar/perfusion plate for hepatotoxicity assays

“…After 10 days of recovery, we observed the expansion of Diff-HLOs, indicated by the appearance of circular organoids, which are Exp-HLOs ( Figures 6D and 6F ). Furthermore, epithelial cells are known to produce pro-inflammatory cytokines to initiate the acute sterile inflammatory response, resulting from damage-associated molecular patterns (DAMPs) recognized by pattern-recognition receptors (PRRs) 31,32 . Interestingly, pro-inflammatory mediators such as IL1 , IL4, IL6, and TNFA as well as HMOX1 cellular stress marker were strongly expressed in Diff-HLOs after acetaminophen treatment ( Figure 6E ).…”

Extracellular Vesicles in Flaviviridae Pathogenesis: Their Roles in Viral Transmission, Immune Evasion, and Inflammation

“…HCV infection becomes chronic in 80-85% of cases and is accompanied by chronic inflammation [102]. In the early stages of liver injury, inflammation plays a role in tissue repair [103], but, over time, excessive inflammation leads to liver cell damage and cell death, with subsequent liver failure, liver fibrosis, regulated by the activation of hepatic stellate cells (HSCs), and hepatocellular carcinoma [104]. EVs can strongly influence these processes and promote the transition from one disease stage to the other through specific immunostimulatory EV cargo [105].…”

Role of Nonalcoholic Fatty Liver Disease in Periodontitis: A Bidirectional Relationship

“…Kupffer cells represent the principal resident macrophages within the liver and the maximum number of mononuclear phagocytes in the human body, constituting the primary cell population regarding the innate immune system [ 72 - 74 ]. The liver possesses its regenerative ability; henceforth, it can often recover from significant damage, yet continuous or chronic damage eventually leads to various chronic liver conditions [ 75 ].…”