Serum metabonomics reveal the effectiveness of human placental mesenchymal stem cell therapy for primary sclerosing cholangitis

  • Stem Cell Res Ther. 2024 Oct 8;15(1):346. doi: 10.1186/s13287-024-03967-y.
Yingduo Yu  1 ,  Qigu Yao  1 ,  Deying Chen  1 ,  Zhehua Zhang  1 ,  Qiaoling Pan  1 ,  Jiong Yu  1  2 ,  Hongcui Cao  3  4 ,  Liang Li  5 ,  Lanjuan Li  1
Affiliations
  • 1. State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.
  • 2. Zhejiang Key Laboratory for Diagnosis and Treatment of Physic-Chemical and Aging-Related Injuries, 79 Qingchun Rd, Hangzhou City, 310003, China.
  • 3. State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China. [email protected].
  • 4. Zhejiang Key Laboratory for Diagnosis and Treatment of Physic-Chemical and Aging-Related Injuries, 79 Qingchun Rd, Hangzhou City, 310003, China. [email protected].
  • 5. Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada.
PMID: 39380092 DOI: 10.1186/s13287-024-03967-y
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.

Keywords
Chemical isotope-labeled liquid chromatography-mass spectrometry; Efficacy biomarker; Mdr2−/− mouse; Mesenchymal stem cell; Metabolomics; Primary sclerosing cholangitis.
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