Characterization and Proteomic Profiling of Hepatocyte-like Cells Derived from Human Wharton's Jelly Mesenchymal Stromal Cells: De Novo Expression of Liver-Specific Enzymes

Overview

Journal Biology (Basel)

Publisher MDPI

Specialty Biology

Date 2025 Feb 26

PMID 40001892

Authors

Melania Lo Iacono

Simona Corrao

Giusi Alberti

Giandomenico Amico

Francesca Timoneri

Eleonora Russo

Annamaria Cucina

Sergio Indelicato

Francesca Rappa

Tiziana Corsello

Salvatore Saieva

Antonino Di Stefano

Francesca Di Gaudio

Pier Giulio Conaldi

Giampiero La Rocca

Affiliations

Soon will be listed here.

Abstract

End-stage liver disease (ESLD), affecting millions worldwide, represents a challenging issue for clinical research and global public health. Liver transplantation is the gold standard therapeutic approach but shows some drawbacks. Hepatocyte transplantation could be a reliable alternative for patient treatment. Mesenchymal stromal cells derived from Wharton's jelly of the umbilical cord (WJ-MSCs) can differentiate into hepatocyte-like cells (HLCs) and show immunomodulatory functions. Due to the increasing demand for fully characterized cell therapy vehicles warranting both the safety and efficacy of treatments, in this work, we extensively characterized WJ-MSCs before and after the application of a hepatocyte-directed differentiation protocol. HLCs exhibited a morphology resembling that of hepatocytes, expressed early and late hepatic markers (α-fetoprotein, albumin, CK18, HNF4-α), and acquired hepatic functions (glycogen synthesis, xenobiotics detoxification), as also revealed by the shotgun proteomics approach. HLCs maintained the same pattern of immunomodulatory molecule expression and mesenchymal markers, other than displaying specific enzymes, suggesting these cells as promising candidates for cellular therapy of ESLD. Our work shed new light on the basic biology of HLCs, suggesting new therapeutic approaches to treat ESLD.

References

Afshari A, Shamdani S, Uzan G, Naserian S, Azarpira N . Different approaches for transformation of mesenchymal stem cells into hepatocyte-like cells. Stem Cell Res Ther. 2020; 11(1):54. PMC: 7007672. DOI: 10.1186/s13287-020-1555-8. View

Koch R, Soler-Alfonso C, Kiely B, Asai A, Smith A, Bali D . Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource. Mol Genet Metab. 2023; 138(3):107525. DOI: 10.1016/j.ymgme.2023.107525. View

Sokal E, Trivedi P, Cheeseman P, Portmann B, Mowat A . The application of quantitative cytochemistry to study the acinar distribution of enzymatic activities in human liver biopsy sections. J Hepatol. 1989; 9(1):42-8. DOI: 10.1016/0168-8278(89)90074-3. View

Kong D, Xu H, Chen M, Yu Y, Qian Y, Qin T . Co-encapsulation of HNF4α overexpressing UMSCs and human primary hepatocytes ameliorates mouse acute liver failure. Stem Cell Res Ther. 2020; 11(1):449. PMC: 7583302. DOI: 10.1186/s13287-020-01962-7. View

Mahmoud R, Bassiouny M, Badawy A, Darwish A, Yahia S, El-Tantawy N . Maternal and neonatal factors' effects on wharton's jelly mesenchymal stem cell yield. Sci Rep. 2024; 14(1):24376. PMC: 11487262. DOI: 10.1038/s41598-024-72386-z. View

Anzalone R, Lo Iacono M, Corrao S, Magno F, Loria T, Cappello F . New emerging potentials for human Wharton's jelly mesenchymal stem cells: immunological features and hepatocyte-like differentiative capacity. Stem Cells Dev. 2009; 19(4):423-38. DOI: 10.1089/scd.2009.0299. View

Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O . HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003; 31(10):890-6. DOI: 10.1016/s0301-472x(03)00110-3. View

Zhao L, Chen S, Shi X, Cao H, Li L . A pooled analysis of mesenchymal stem cell-based therapy for liver disease. Stem Cell Res Ther. 2018; 9(1):72. PMC: 5863358. DOI: 10.1186/s13287-018-0816-2. View

Liu M, Sun L . Liver Transplantation for Glycogen Storage Disease Type IV. Front Pediatr. 2021; 9:633822. PMC: 7933444. DOI: 10.3389/fped.2021.633822. View

10.

Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z . Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012; 1(10):725-31. PMC: 3659658. DOI: 10.5966/sctm.2012-0034. View

11.

Lu D, Xie Q, Wu B . N-glucuronidation catalyzed by UGT1A4 and UGT2B10 in human liver microsomes: Assay optimization and substrate identification. J Pharm Biomed Anal. 2017; 145:692-703. DOI: 10.1016/j.jpba.2017.07.037. View

12.

Li Y, Wu Q, Wang Y, Li L, Chen F, Shi Y . Immunogenicity of hepatic differentiated human umbilical cord mesenchymal stem cells promoted by porcine decellularized liver scaffolds. Xenotransplantation. 2017; 24(1). DOI: 10.1111/xen.12287. View

13.

Campard D, Lysy P, Najimi M, Sokal E . Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells. Gastroenterology. 2008; 134(3):833-48. DOI: 10.1053/j.gastro.2007.12.024. View

14.

Soderdahl T, Kuppers-Munther B, Heins N, Edsbagge J, Bjorquist P, Cotgreave I . Glutathione transferases in hepatocyte-like cells derived from human embryonic stem cells. Toxicol In Vitro. 2007; 21(5):929-37. DOI: 10.1016/j.tiv.2007.01.021. View

15.

Houten S, Denis S, Argmann C, Jia Y, Ferdinandusse S, Reddy J . Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids. J Lipid Res. 2012; 53(7):1296-303. PMC: 3371241. DOI: 10.1194/jlr.M024463. View

16.

Bharti D, Shivakumar S, Park J, Ullah I, Subbarao R, Park J . Comparative analysis of human Wharton's jelly mesenchymal stem cells derived from different parts of the same umbilical cord. Cell Tissue Res. 2017; 372(1):51-65. PMC: 5862947. DOI: 10.1007/s00441-017-2699-4. View

17.

Anzalone R, Lo Iacono M, Loria T, Di Stefano A, Giannuzzi P, Farina F . Wharton's jelly mesenchymal stem cells as candidates for beta cells regeneration: extending the differentiative and immunomodulatory benefits of adult mesenchymal stem cells for the treatment of type 1 diabetes. Stem Cell Rev Rep. 2010; 7(2):342-63. DOI: 10.1007/s12015-010-9196-4. View

18.

DAVEAU M, JEAN L, Soury E, Olivier E, Masson S, Lyoumi S . Hepatic and extra-hepatic transcription of inter-alpha-inhibitor family genes under normal or acute inflammatory conditions in rat. Arch Biochem Biophys. 1998; 350(2):315-23. DOI: 10.1006/abbi.1997.0515. View

19.

Guengerich F . Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions. Chem Res Toxicol. 2016; 30(1):2-12. PMC: 5293730. DOI: 10.1021/acs.chemrestox.6b00226. View

20.

Ventura G, De Bandt J, Segaud F, Perret C, Robic D, Levillain O . Overexpression of ornithine aminotransferase: consequences on amino acid homeostasis. Br J Nutr. 2008; 101(6):843-51. DOI: 10.1017/S0007114508043389. View