Deciphering miRNA-mediated regulation of liver regeneration: New insights

Xia & He Publishing Inc.Jul 29 2024

The liver, a vital organ involved in numerous essential physiological processes such as bile production, plasma protein synthesis, nutrient absorption, detoxification, vitamin storage, macronutrient metabolism, and immune support, has a remarkable regenerative capacity. The liver parenchyma consists primarily of hepatocytes, accounting for approximately 80% of its mass, and cholangiocytes. The non-parenchymal cells include hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and resident macrophages known as Kupffer cells. Adult hepatocytes, usually in a quiescent state, can rapidly re-enter the cell cycle following acute injuries such as drug-induced damage or hepatic resection. Effective liver regeneration (LR) is critical for restoring normal liver size and function, and impaired LR can result in liver failure and death.

MicroRNAs and liver regeneration

MicroRNAs (miRNAs) are pivotal regulators of LR. Despite numerous studies highlighting their importance, the specific molecular mechanisms involved in miRNA-mediated regulation of LR are not fully understood. Recent efforts have focused on elucidating these mechanisms, driven by the potential therapeutic applications of miRNAs for treating diseases characterized by impaired LR. This review summarizes recent studies from January 2022 to December 2023, shedding light on how miRNAs regulate LR after acute liver injury induced by 2/3 partial hepatectomy (PH) or acetaminophen (APAP) overdose. Several miRNAs have emerged as potential molecular targets for tissue repair and functional recovery of the liver.

Mechanisms of miRNA regulation

1. Circ-RBM23 and miRNA139-5p:
   • Recent findings indicate that circ-RBM23 promotes LR by sequestering cytoplasmic miRNA139-5p, enhancing our understanding of circRNA activity. While miRNAs are generally viewed as negative regulators of their target mRNAs, miRNA182-5p has been found to promote LR by upregulating Cyp7a.
2. Mesenchymal Stem Cell-Derived Extracellular Vesicles:
   • Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been shown to enhance LR post-2/3 PH by releasing miRNAs that inhibit gene expression to promote an anti-inflammatory response. Given that MSCs-EVs administration has no hepatotoxic side effects, this approach holds promise as a therapeutic strategy for promoting LR.
3. miR21 Downregulation:
   • In the context of chemical injury, particularly APAP overdose, downregulation of miR21 has been shown to improve autophagy and haemostasis. However, further research is necessary to optimize miRNA-based therapies for clinical use.

Therapeutic potential and challenges

miRNAs represent promising therapeutic tools for treating liver diseases due to their high stability and detectability in the bloodstream. These properties make them superior biomarkers for early diagnosis, prognosis, and evaluation of liver diseases compared to conventional biomarkers. However, miRNA-based therapeutic options require careful development due to their cell-type-specific functions and the potential for off-target effects. Future studies must focus on characterizing the molecular mechanisms underlying miRNA actions to improve therapeutic efficacy.

Conclusions

The reviewed studies demonstrate that miRNAs are deeply involved in controlling LR by regulating gene expression associated with cell proliferation and liver repair. In the 2/3 PH model, miRNA-mediated gene regulation is evident in each phase of LR. Changes in miRNA expression during the initiation and proliferation phases can either inhibit or activate proliferation signaling, highlighting their dual role. The termination phase, less studied compared to the other phases, involves upregulation of miRNAs that promote LR termination by triggering pro-apoptotic signaling while inhibiting proliferation signaling. Two recent studies have shown the potential of miRNAs as therapeutic tools for treating APAP-mediated liver injury. While further understanding of miRNA-dependent molecular strategies is necessary, these findings have identified new potential molecular targets for diagnosing and treating liver diseases.