Key Takeaways & Executive Findings
- •• hP-MSC therapy effectively ameliorates PSC in Mdr2−/− mice, as evidenced by improved liver histology, reduced liver enzymes, and decreased inflammatory factors. • Serum metabolomics identified 41 differentially expressed metabolites, with key pathways involving bile acid metabolism, lipid metabolism, and hydroxyproline metabolism. • Eight serum metabolites were identified as potential efficacy biomarkers, with four decreasing and four increasing after hP-MSC treatment, offering non-invasive monitoring options. • The study provides preclinical evidence supporting the therapeutic potential of hP-MSCs for PSC and highlights metabolic regulatory mechanisms underlying their efficacy.
Abstract
Background The metabolic patterns of human placental-derived mesenchymal stem cell (hP-MSC) treatment for primary sclerosing cholangitis (PSC) remain unclear, and therapeutic effects significantly vary due to individual differences. Therefore, it is crucial to investigate the serological response to hP-MSC transplantation through small molecular metabolites and identify easily detectable markers for efficacy evaluation. Methods Using Mdr2−/− mice as a PSC model and Mdr2+/+ mice as controls, the efficacy of hP-MSC treatment was assessed based on liver pathology, liver enzymes, and inflammatory factors. Serum samples were collected for 12C-/13C-dansylation and DmPA labeling LC–MS analysis to investigate changes in metabolic pathways after hP-MSC treatment. Key metabolites and regulatory enzymes were validated by qRT-PCR and Western blotting. Potential biomarkers of hP-MSC efficacy were identified through correlation analysis and machine learning. Results Collectively, the results of the liver histology, serum liver enzyme levels, and inflammatory factors supported the therapeutic efficacy of hP-MSC treatment. Based on significant differences, 41 differentially expressed metabolites were initially identified; these were enriched in bile acid, lipid, and hydroxyproline metabolism. After treatment, bile acid transport was accelerated, whereas bile acid production was reduced; unsaturated fatty acid synthesis was upregulated overall, with increased FADS2 and elongase expression and enhanced fatty acid β-oxidation; hepatic proline 4-hydroxylase expression was decreased, leading to reduced hydroxyproline production. Correlation analysis of liver enzymes and metabolites, combined with time trends, identified eight potential biomarkers: 2-aminomuconate semialdehyde, l-1-pyrroline-3-hydroxy-5-carboxylic acid, l-isoglutamine, and maleamic acid were more abundant in model mice but decreased after hP-MSC treatment. Conversely, 15-methylpalmitic, eicosenoic, nonadecanoic, and octadecanoic acids were less abundant in model mice but increased after hP-MSC treatment. Conclusions This study revealed metabolic regulatory changes in PSC model mice after hP-MSC treatment and identified eight promising biomarkers, providing preclinical evidence to support therapeutic applications of hP-MSC.
1. Introduction
Primary sclerosing cholangitis (PSC) is a liver condition characterized by damage to bile ducts within or outside the liver, or both. The disease process involves an interaction of inflammation, fibrosis, and cholestasis [1]. No genetic or environmental factors are associated with or known to trigger PSC [2, 3]. Several drugs targeting biliary components, immunomodulation, fibrosis, or the gut microbiome have been tested in PSC patients [4, 5]. Ursodeoxycholic acid (UDCA) has limited efficacy in altering the long-term course of the disease and improving survival [6]. Immunosuppressive medications, including steroids, azathioprine, and cyclosporine, are effective in specific cases according to some reports; however, their overall efficacy remains uncertain and they have substantial adverse effects [7]. Currently, liver transplantation remains the sole definitive treatment. The 10-year recurrence rate after liver transplantation is approximately 20% [8]. Consequently, it is imperative to develop novel therapeutic interventions. Recently, cellular therapy, particularly mesenchymal stem cell (MSC) therapy [9, 10], has received considerable attention as a promising therapeutic modality.
Friedenstein et al. first identified MSCs in mouse bone marrow, and subsequent evidence has demonstrated that they originate from pericytes and adventitial progenitor cells in almost all tissues [11, 12]. Human placenta-derived mesenchymal stem cells (hP-MSCs), found in the fetal membranes of the full-term placenta, are easily obtained using non-invasive techniques. Studies have investigated the potential therapeutic applications of MSCs in mouse models of PSC and organoid models [13–15]. MSCs ameliorate bile duct hyperplasia, peribiliary fibrosis, and inflammation in experimental models, suggesting their potential as a novel treatment for PSC.
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Yingduo Yu, Qigu Yao, Deying Chen, Zhehua Zhang, Qiaoling Pan, Jiong Yu, Hongcui Cao, Liang Li, Lanjuan Li (2026). Serum metabonomics reveal the effectiveness of human placental mesenchymal stem cell therapy for primary sclerosing cholangitis. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-024-03967-y
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Frequently Asked Questions
What is primary sclerosing cholangitis (PSC)?
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammation and fibrosis of the bile ducts, leading to cholestasis and eventually cirrhosis. It has no known cure, and liver transplantation is often the only definitive treatment.
How does human placental mesenchymal stem cell (hP-MSC) therapy work for PSC?
hP-MSC therapy is believed to exert immunomodulatory and regenerative effects. In this study, hP-MSC treatment in a PSC mouse model improved liver pathology, reduced liver enzymes and inflammation, and modulated metabolic pathways, including bile acid and lipid metabolism.
What are the potential biomarkers for hP-MSC efficacy in PSC?
The study identified eight serum metabolites as potential biomarkers: 2-aminomuconate semialdehyde, l-1-pyrroline-3-hydroxy-5-carboxylic acid, l-isoglutamine, and maleamic acid decreased after treatment, while 15-methylpalmitic, eicosenoic, nonadecanoic, and octadecanoic acids increased.
What metabolic pathways are affected by hP-MSC treatment in PSC?
hP-MSC treatment affects bile acid metabolism (accelerating transport and reducing production), lipid metabolism (upregulating unsaturated fatty acid synthesis and β-oxidation), and hydroxyproline metabolism (reducing production via decreased proline 4-hydroxylase expression).
What is the significance of this study for PSC treatment?
This study provides preclinical evidence that hP-MSC therapy is effective in a PSC mouse model and identifies potential biomarkers for monitoring treatment response, which could facilitate the development of non-invasive efficacy assessment and personalized therapy in future clinical applications.
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