EGFR-mediated crosstalk between vascular endothelial cells and hepatocytes promotes Piezo1-dependent liver regeneration
Open accessAbstract
Hepatocyte proliferation is essential for recovering liver function after injury. In liver surgery, the mechanical stimulation induced by hemodynamic changes triggers vascular endothelial cells (VECs) to secrete large amounts of cytokines that enhance hepatocyte proliferation and play a pivotal role in liver regeneration (LR). Piezo1, a critical mechanosensory ion channel, can detect and convert mechanical forces into chemical signals, importing external stimuli into cells and triggering downstream biological effects. However, the precise role of Piezo1 in VECs, especially in terms of mediating LR, remains unclear. Here, we report on a potential mechanism by which early changes in hepatic portal hemodynamics activate Piezo1 in VECs to promote hepatocyte proliferation during the process of LR induced by portal vein ligation in rats. In this LR model, hepatocyte proliferation is mainly distributed in zone 1 and zone 2 of liver lobules at 24-48 h after surgery, while only a small number of Ki67-positive hepatocytes were observed in zone 3. Activation of Piezo1 promotes increased secretion of epiregulin and amphiregulin from VECs via the PKC/ERK1/2 axis, further activating epidermal growth factor receptor (EGFR) and ERK1/2 signals in hepatocytes and promoting proliferation. In the liver lobules, the expression of EGFR in hepatocytes of zone 1 and zone 2 is significantly higher than that in zone 3. The EGFR inhibitor gefitinib inhibits LR by suppressing the proliferation of hepatocytes in the middle zone. These data provide a theoretical basis for the regulation of LR through chemical signals mediated by mechanical stimulation.
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The direction of regenerative processes following liver tissue damage is determined by changes in portal pressure and flow.
“Our long-term studies, supported by literature data, indicate that the direction of regenerative processes following liver tissue damage is determined by changes in portal pressure and flow—which act as mechanical and physiological determinants[4,9,11,12].”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [4]
The Introduction says hemodynamic changes help initiate and regulate liver regeneration, and the Results report regeneration on the non-ligated side of a rat portal-vein-ligation model. The paper supports a role for portal flow and mechanical forces, but it does not establish that changes in both portal pressure and flow determine the direction of regenerative processes after liver tissue damage generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAfter resection of more than 50% of the liver, the blood supply previously directed to the entire liver is redistributed to the remaining liver tissue, resulting in increased pressure and flow that triggers proliferative (hyperplastic) regeneration.
“In contrast, after resection more than 50% of the liver, the blood supply previously directed to the entire liver, is redistributed to the remaining liver tissue, resulting in increased pressure and flow. This triggers a cascade of cellular proliferation, leading to proliferative (hyperplastic) regeneration[4].”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [4]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAREG and EREG activate EGFR signaling in hepatocytes, driving their proliferation, especially in liver zones 1 and 2.
“These ligands activate epidermal growth factor receptor (EGFR) signaling in hepatocytes driving their proliferation, especially in liver zones 1 and 2[4,20].”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [4]
The Results section reports that AREG and EREG activate EGFR and promote proliferation in LO2 hepatocytes. It also reports higher EGFR expression in zones 1 and 2 than in zone 3, but does not show that AREG- and EREG-driven proliferation occurs especially in those zones; the proposed link between ligand secretion and regional proliferation is presented as a suggestion. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPiezo1 upregulates the expression and secretion of amphiregulin (AREG) and epiregulin (EREG) via the PKC/ERK1/2 signaling axis.
“Piezo1, in turn, upregulates the expression and secretion of amphiregulin (AREG) and epiregulin (EREG) via the protein kinase C/extracellular signal-regulated kinases 1 and 2 (PKC/ERK1/2) signaling axis[4].”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [4]
In the Results section on PKC and ERK1/2 regulation in vascular endothelial cells, Yoda1-induced Piezo1 activation increased AREG and EREG expression, and PKC and ERK1/2 inhibitors blocked that increase. The same section reports that Piezo1 knockdown inhibited AREG and EREG secretion. It does not establish that secretion itself is mediated through the PKC/ERK1/2 axis. (LLM, conf=0.83)
Experimental — accuracy not yet measured
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- Authors
- Hu, Y., Du, G., Li, C., Wang, R., Liu, J., Wang, Y., & Dong, J.
- Affiliations
- Jilin University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Tsinghua University (CN)
- Corresponding author
- Liu, Juan
- Wang, Yunfang
- Dong, Jiahong
- Venue
- Genes & Diseases
- Publisher
- Elsevier BV
- Published
- 2025-05
- Volume
- 12
- Issue
- 3
- Pages
- 101321
- ISSN
- 2352-3042 (ISSN-L)
- PMC
- PMC11904541
- OpenAlex
- W4396732101
- Cited by
- 7
- References
- 29
- Citations by year
- 2026: 4 · 2025: 3
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Genes & Diseases (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Key Research and Development Program of China Stem Cell and Translational Research
- National Natural Science Foundation of China
- CAMS Innovation Fund for Medical Sciences
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- liver regeneration, Piezo1, vascular endothelial cells, hepatocyte proliferation, EGFR signaling, epiregulin, amphiregulin, portal vein ligation, hemodynamic changes, mechanosensing, gefitinib
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