Comprehensive Evaluation of the Mechanism of Human Adipose Mesenchymal Stem Cells Ameliorating Liver Fibrosis by Transcriptomics and Metabolomics Analysis

Overview

Journal Sci Rep

Specialty Science

Date 2024 Aug 28

PMID 39198546

Authors

Guibao Ji

Zilong Zhang

Xinze Wang

Qiuxia Guo

Erlei Zhang

Chuanjiang Li

Affiliations

Soon will be listed here.

Abstract

Liver fibrosis is a chronic liver disease with progressive wound healing reaction caused by liver injury. Currently, there is no FDA approved drugs for liver fibrosis. Human adipose mesenchymal stem cells (hADSCs) have shown remarkable therapeutic effects in liver diseases. However, few studies have evaluated the therapeutic role of hADSCs in liver fibrosis, and the detailed mechanism of action is unknown. Here, we investigated the in vitro and in vivo anti-fibrosis efficacy of hADSCs and identified important metabolic changes and detailed mechanisms through transcriptomic and metabolomic analyses. We found that hADSCs could inhibit the proliferation of activated hepatic stellate cells (HSCs), promote their apoptosis, and effectively inhibit the expression of pro-fibrotic protein. It can significantly reduce collagen deposition and liver injury, improve liver function and alleviate liver inflammation in cirrhotic mouse models. In addition, transcriptome analysis revealed that the key mechanism of hADSCs against liver fibrosis is the regulation of AGE-RAGE signaling pathway. Metabolic analysis showed that hADSCs influenced changes of metabolites in lipid metabolism. Therefore, our study shows that hADSCs could reduce the activation of hepatic stellate cells and inhibit the progression of liver fibrosis, which has important potential in the treatment of liver fibrosis as well as other refractory chronic liver diseases.

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References

Thomou T, Mori M, Dreyfuss J, Konishi M, Sakaguchi M, Wolfrum C . Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature. 2017; 542(7642):450-455. PMC: 5330251. DOI: 10.1038/nature21365. View

Urtasun R, Lopategi A, George J, Leung T, Lu Y, Wang X . Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin α(V)β(3) engagement and PI3K/pAkt/NFκB signaling. Hepatology. 2011; 55(2):594-608. PMC: 3561739. DOI: 10.1002/hep.24701. View

Roehlen N, Crouchet E, Baumert T . Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells. 2020; 9(4). PMC: 7226751. DOI: 10.3390/cells9040875. View

Lou G, Yang Y, Liu F, Ye B, Chen Z, Zheng M . MiR-122 modification enhances the therapeutic efficacy of adipose tissue-derived mesenchymal stem cells against liver fibrosis. J Cell Mol Med. 2017; 21(11):2963-2973. PMC: 5661245. DOI: 10.1111/jcmm.13208. View

Han H, Lee H, You D, Nguyen V, Song D, Oh B . Human adipose stem cell-derived extracellular nanovesicles for treatment of chronic liver fibrosis. J Control Release. 2020; 320:328-336. DOI: 10.1016/j.jconrel.2020.01.042. View

Barcena-Varela M, Paish H, Alvarez L, Uriarte I, Latasa M, Santamaria E . Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis. Gut. 2020; 70(2):388-400. DOI: 10.1136/gutjnl-2019-320205. View

Zhang J, Zhou S, Zhou Y, Feng F, Wang Q, Zhu X . Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model. PLoS One. 2014; 9(12):e114670. PMC: 4264768. DOI: 10.1371/journal.pone.0114670. View

Koch M, Lehnhardt A, Hu X, Brunswig-Spickenheier B, Stolk M, Brocker V . Isogeneic MSC application in a rat model of acute renal allograft rejection modulates immune response but does not prolong allograft survival. Transpl Immunol. 2013; 29(1-4):43-50. DOI: 10.1016/j.trim.2013.08.004. View

Deng L, Mohan T, Chang T, Gonzalez G, Wang Y, Kwon Y . Double-layered protein nanoparticles induce broad protection against divergent influenza A viruses. Nat Commun. 2018; 9(1):359. PMC: 5783933. DOI: 10.1038/s41467-017-02725-4. View

10.

Jiang L, Zhang S, Hu H, Yang J, Wang X, Ma Y . Exosomes derived from human umbilical cord mesenchymal stem cells alleviate acute liver failure by reducing the activity of the NLRP3 inflammasome in macrophages. Biochem Biophys Res Commun. 2018; 508(3):735-741. DOI: 10.1016/j.bbrc.2018.11.189. View

11.

Massey V, Dolin C, Poole L, Hudson S, Siow D, Brock G . The hepatic "matrisome" responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice. Hepatology. 2016; 65(3):969-982. PMC: 5319876. DOI: 10.1002/hep.28918. View

12.

Kanehisa M . Toward understanding the origin and evolution of cellular organisms. Protein Sci. 2019; 28(11):1947-1951. PMC: 6798127. DOI: 10.1002/pro.3715. View

13.

Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L . Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2012; 22(6):845-54. PMC: 3585469. DOI: 10.1089/scd.2012.0395. View

14.

Volarevic V, Gazdic M, Markovic B, Jovicic N, Djonov V, Arsenijevic N . Mesenchymal stem cell-derived factors: Immuno-modulatory effects and therapeutic potential. Biofactors. 2017; 43(5):633-644. DOI: 10.1002/biof.1374. View

15.

Qu Y, Zhang Q, Cai X, Li F, Ma Z, Xu M . Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation. J Cell Mol Med. 2017; 21(10):2491-2502. PMC: 5618698. DOI: 10.1111/jcmm.13170. View

16.

Wilson E, Rosenthal E, Kattakuzhy S, Tang L, Kottilil S . Clinical Laboratory Testing in the Era of Directly Acting Antiviral Therapies for Hepatitis C. Clin Microbiol Rev. 2016; 30(1):23-42. PMC: 5217793. DOI: 10.1128/CMR.00037-16. View

17.

Asmani M, Velumani S, Li Y, Wawrzyniak N, Hsia I, Chen Z . Fibrotic microtissue array to predict anti-fibrosis drug efficacy. Nat Commun. 2018; 9(1):2066. PMC: 5970268. DOI: 10.1038/s41467-018-04336-z. View

18.

Sun J, Chen Y, Wang T, Ali W, Ma Y, Yuan Y . Baicalin and N-acetylcysteine regulate choline metabolism via TFAM to attenuate cadmium-induced liver fibrosis. Phytomedicine. 2024; 125:155337. DOI: 10.1016/j.phymed.2024.155337. View

19.

Puche J, Saiman Y, Friedman S . Hepatic stellate cells and liver fibrosis. Compr Physiol. 2013; 3(4):1473-92. DOI: 10.1002/cphy.c120035. View

20.

Bruden D, McMahon B, Townshend-Bulson L, Gounder P, Gove J, Plotnik J . Risk of end-stage liver disease, hepatocellular carcinoma, and liver-related death by fibrosis stage in the hepatitis C Alaska Cohort. Hepatology. 2017; 66(1):37-45. PMC: 5481475. DOI: 10.1002/hep.29115. View