Abstract
Abstract
Background
Chronic liver injury is accompanied by vascular and endothelial dysfunction with increased vascular leakiness, which can aggravate fibrotic remodeling and limit regeneration. In our previous reports, phosphatase of regenerating liver-1 (PRL-1)-overexpressing placenta-derived mesenchymal stem cells (PD-MSCs
PRL−1
) improved the balance between profibrotic and pro-repair signaling in chronic liver injury. However, whether PD-MSCs
PRL−1
improve endothelial function and promote regenerative responses via hepatocyte growth factor (HGF) remains unclear. Therefore, we investigated whether PD-MSCs
PRL−1
promote liver repair by strengthening an HGF-centered paracrine program and endothelial-supportive effects.
Methods
A thioacetamide (TAA)-induced rat liver injury model was established in 7-week-old female Sprague-Dawley rats using TAA (150 mg/kg, twice a week, 12 weeks), then received intravenous transplantation of either naïve PD-MSCs or PD-MSCs
PRL−1
(2×10
6
cells/ea). Hepatic localization of transplanted cells was assessed by PKH67 labeling and detection of human-specific hAlu sequences. Liver injury and function were evaluated using serum biomarkers and hepatic regeneration-associated transcripts. Vascular-associated readouts included portal vein architecture and quantification of extravascular fluorescence after intravenous injection of fluorescein-labeled 70-kDa dextran. In vitro, TAA-stressed or tivantinib-treated human umbilical vein endothelial cells (HUVECs) were co-cultured with PD-MSCs or PD-MSCs
PRL−1
and assessed by tube formation and FITC-dextran permeability. VEGF- and endothelial-associated markers (VEGF/VEGFR2, ERG, ASEF) were evaluated by ELISA, qRT-PCR, immunofluorescence, and immunoblotting.
Results
PD-MSCs
PRL−1
transplantation improved serum indicators of liver injury and function, with hepatic localization confirmed by PKH67 and hAlu detection. PRL-1 enhancement increased HGF expression and was associated with increased c-Met activation in injured liver. Vascular-related gene expression was improved, including attenuation of portal vein dilation and reduced extravascular dextran signal, accompanied by coordinated changes in VEGF/VEGFR2 signaling and endothelial-associated markers. In HUVEC assays, PD-MSCs
PRL−1
co-culture restored endothelial network organization and reduced permeability under TAA stress and partially counteracted tivantinib-associated endothelial dysfunction, with concordant recovery of c-Met phosphorylation-linked readouts.
Conclusions
PD-MSCs
PRL−1
is associated with improved liver repair and endothelial-supportive responses consistent with hepatic vascular stabilization during fibrotic liver injury. These findings support further development of PRL-1 enhancement as a strategy to strengthen PD-MSC-based therapies targeting vascular dysfunction in chronic liver injury.