Electroacupuncture in liver regeneration: a Chinese traditional medicine approach to enhancing liver regeneration

We read with great interest the paper by Yang et al., published in Advanced Science (1), which presents an intriguing exploration into the use of electroacupuncture (EA) to enhance liver regeneration. This study primarily investigates the roles of the vagus nerve and hepatic macrophages in facilitating liver regeneration, focusing on the brain-liver axis and the underlying mechanisms.

The liver, as an organ capable of regeneration, relies on effective regenerative capacity to ensure proper repair and restoration of functional liver mass following injury (2). The process of liver cell regeneration is a complex interplay involving both humoral factors and neural regulation. Numerous studies have centered on the role of signaling molecules in liver regeneration, particularly following injury. These include vascular endothelial growth factor (VEGF), angiopoietins, transforming growth factor, and adipose tissue (3-5). However, beyond these molecular pathways, the autonomic nervous system, particularly the vagus nerve, has been increasingly recognized as a significant regulator of liver regeneration. Since the pioneering study by Kato et al. in 1983, which demonstrated that vagotomy inhibits liver regeneration, the vagus nerve has garnered much attention as a key player in this regenerative process (6).

Yang et al.’s study contributes further insights into the brain-liver axis, a concept that emphasizes the communication between the central nervous system and liver function. Their research demonstrates that EA at the ST36 acupoint significantly promotes liver regeneration in a 70% partial hepatectomy mouse model, evidenced by increased hepatocyte proliferation and enhanced liver function. The proposed mechanism involves EA activation of cholinergic neurons in the brain, which, in turn, boosts the release of acetylcholine from vagal nerve terminals in the liver. This activation triggers the interleukin 6 (IL-6) signaling pathway, mediated through the signal transducer and activator of transcription 3 (STAT3), ultimately promoting hepatocyte proliferation. Notably, this mechanism is contingent on the presence of hepatic macrophages and is closely linked to the function of the vagus nerve.

The findings presented by Yang et al. provide valuable new insights into the neural regulation of liver regeneration, a field that has attracted significant research interest in recent years. Prior studies examining the vagus nerve’s role in liver regeneration often employed vagotomy to study its function by comparing liver regeneration outcomes in vagotomized animals versus controls (7). In contrast, the present study highlights the potential benefits of increasing vagal tone through electrical stimulation, offering new perspectives on how acupuncture could serve as a practical clinical intervention to support liver disease treatment. These findings may also have significant implications for improving post-hepatectomy outcomes in patients who suffer from impaired liver regeneration, a common challenge in liver surgery. Despite the valuable contributions of this study, certain limitations warrant further discussion.

First, while the study convincingly demonstrates that EA can stimulate liver regeneration via the vagus nerve, we believe that including additional control groups, employing alternative methods of vagal nerve excitation, could provide further clarity regarding EA’s unique role in this context. The authors show that vagal stimulation enhances liver regeneration, but it is important to note that electrical stimulation is not the only means of increasing vagal tone. For example, pharmacological agents such as bethanechol can stimulate visceral vagal activity (8). Thus, it would be worth exploring whether non-electrical stimulation methods could similarly promote vagal nerve activation and whether these approaches might offer better clinical applicability. While neural electrical stimulation presents several advantages, such as rapid onset and targeted action, pharmacological interventions might come with gastrointestinal side effects and additional metabolic burdens on the liver (9). Comparing different methods of vagal nerve modulation, such as pharmacological or non-invasive techniques, could provide a more comprehensive understanding of the specific benefits and limitations of EA. The absence of such comparisons limits the current understanding of EA’s specificity and mechanism of action.

Second, although the study offers insights into the neural mechanisms driving liver regeneration, there remains room for deeper investigation into these mechanisms, particularly concerning hepatocyte regeneration. We are especially interested in exploring the neural pathways involved in stimulating liver regeneration. Existing research has already validated the role of the IL-6-STAT3-FoxM1 pathway in mediating the “vagus nerve-macrophage-hepatocyte” axis in liver resection models, where FoxM1 influences key proteins involved in cell cycle progression (7,10). Therefore, while the study elucidates a plausible pathway, we believe its novelty in mechanistic terms could be further enhanced. Additionally, IL-6, as an auxiliary mitogen, does not independently induce hepatocyte DNA replication or liver enlargement when injected alone (4). However, the results of the vagotomy experiments suggest that the effects of vagal nerve stimulation may not be confined to the STAT3-IL-6 pathway alone. Complete mitogens, such as hepatocyte growth factor (HGF) or epidermal growth factor receptor (EGFR) ligands, may also play essential roles in regulating hepatocyte proliferation through neural mechanisms.

At the same time, the promoting effect of vagus nerve stimulation on liver regeneration can currently be observed in the injury model of acute liver resection, but there are many types of liver injury models, such as acute liver injury [CCL4 model, 1,4-dihydro-2,4,6-trimethyl-pyridine-3,5-dicarboxylate (DDC) diet], liver fibrosis model, fatty liver model, etc. (11). Since liver damage can vary significantly in clinical scenarios, it is important to determine whether vagal nerve stimulation can be universally applied across different injury contexts.

Third, the lack of significant differences between the “hepatectomy (PH) + vagotomy (HV) + EA” group and the “PH + HV” group may be attributable to the short observation period. In this study, the authors only examined liver regeneration within 48 hours after hepatectomy. However, in liver transplantation, where the vagus nerve is severed, autonomic reinnervation of the liver does not occur until at least 3 days post-operation in rat models (12,13). Therefore, we hope to confirm whether it still has the ability to promote liver regeneration after liver autonomic reinnervation. Additionally, nerve stimulation has been shown to promote nerve regeneration and plasticity in nerve injury models, prompting us to consider whether EA at the ST36 acupoint might accelerate reinnervation following vagotomy (14). Therefore, we eagerly anticipate the authors’ long-term liver regeneration results for the “hepatectomy + vagotomy + EA” group. These results will help assess whether EA can expedite autonomic reinnervation and post-reinnervation liver regeneration. Such findings could have significant clinical implications, particularly in preventing small-for-size syndrome in post-liver transplantation patients.

We highly appreciate this study on EA-promoted liver regeneration, which provides new applications and theoretical support for traditional Chinese medicine. Although the current research does not answer all the questions regarding the vagus nerve and liver regeneration, it offers a potential postoperative management strategy for patients undergoing extensive hepatectomy, such as associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or hepatic carcinoma resections, where promoting hepatocyte proliferation is crucial.

Acknowledgments

Funding: This work was supported by grants from Haihe Laboratory of Cell Ecosystem Innovation Fund (No. 22HHXBSS00012).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-516/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Yang L, Zhou Y, Huang Z, et al. Electroacupuncture Promotes Liver Regeneration by Activating DMV Acetylcholinergic Neurons-Vagus-Macrophage Axis in 70% Partial Hepatectomy of Mice. Adv Sci (Weinh) 2024;11:e2402856. [Crossref] [PubMed]
2. Rassam F, Olthof PB, Takkenberg B, et al. Functional assessment of liver regeneration after major hepatectomy. Hepatobiliary Surg Nutr 2022;11:530-8. [Crossref] [PubMed]
3. Deeb AA, Settmacher U, Ardelt M, et al. Adipose tissue induces a better liver regeneration after living liver donation in normal weight donors. Hepatobiliary Surg Nutr 2023;12:341-50. [Crossref] [PubMed]
4. Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol 2021;18:40-55. [Crossref] [PubMed]
5. Kiba T. The role of the autonomic nervous system in liver regeneration and apoptosis--recent developments. Digestion 2002;66:79-88. [Crossref] [PubMed]
6. Kato H, Shimazu T. Effect of autonomic denervation on DNA synthesis during liver regeneration after partial hepatectomy. Eur J Biochem 1983;134:473-8. [Crossref] [PubMed]
7. Izumi T, Imai J, Yamamoto J, et al. Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation. Nat Commun 2018;9:5300. [Crossref] [PubMed]
8. Renz BW, Tanaka T, Sunagawa M, et al. Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. Cancer Discov 2018;8:1458-73. [Crossref] [PubMed]
9. Marucci G, Buccioni M, Ben DD, et al. Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology 2021;190:108352. [Crossref] [PubMed]
10. Xie G, Song Y, Li N, et al. Myeloid peroxisome proliferator-activated receptor α deficiency accelerates liver regeneration via IL-6/STAT3 pathway after 2/3 partial hepatectomy in mice. Hepatobiliary Surg Nutr 2022;11:199-211. [Crossref] [PubMed]
11. Forbes SJ, Newsome PN. Liver regeneration - mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol 2016;13:473-85. [Crossref] [PubMed]
12. Boon AP, Hubscher SG, Lee JA, et al. Hepatic reinnervation following orthotopic liver transplantation in man. J Pathol 1992;167:217-22. [Crossref] [PubMed]
13. Takahashi T, Kakita A, Sakamoto I, et al. Immunohistochemical and electron microscopic study of extrinsic hepatic reinnervation following orthotopic liver transplantation in rats. Liver 2001;21:300-8. [Crossref] [PubMed]
14. Angelin LG, Carreño MNP, Otoch JP, et al. Regeneration and Plasticity Induced by Epidural Stimulation in a Rodent Model of Spinal Cord Injury. Int J Mol Sci 2024;25:9043. [Crossref] [PubMed]