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Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside

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Abstract

Liver diseases impose a huge burden worldwide. Although hepatocyte transplantation has long been considered as a potential strategy for treating liver diseases, its clinical implementation has created some obvious limitations. As an alternative strategy, cell therapy, particularly mesenchymal stem cell (MSC) transplantation, is widely used in treating different liver diseases, including acute liver disease, acute-on-chronic liver failure, hepatitis B/C virus, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Here, we summarize the status of MSC transplantation in treating liver diseases, focusing on the therapeutic mechanisms, including differentiation into hepatocyte-like cells, immunomodulating function with a variety of immune cells, paracrine effects via the secretion of various cytokines and extracellular vesicles, and facilitation of homing and engraftment. Some improved perspectives and current challenges are also addressed. In summary, MSCs have great potential in the treatment of liver diseases based on their multi-faceted characteristics, and more accurate mechanisms and novel therapeutic strategies stemming from MSCs will facilitate clinical practice.

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Abbreviations

OLT :

Orthotopic liver transplantation

MSC :

Mesenchymal stem cell

HLCs :

hepatocyte-like cells

CD :

cluster of differentiation

BM :

bone marrow

AD :

adipose tissue

UC :

umbilical cord

EV :

extracellular vesicle

HGF :

hepatocyte growth factor

EGF :

epidermal growth factor

HNF :

hepatocyte nuclear factor

FGF :

fibroblast growth factor

ITS :

insulin-transferrin selenium

OSM :

oncostatin M

DMSO :

dimethyl sulfoxide

CK-18 :

cytokeratin 18

CYP :

cytochrome p450

TNF-α :

tumor necrosis factor-alpha

DCs :

dendritic cells

NK :

natural killer

Tregs :

regulatory T cells

MMP-9 :

matrix metalloproteinase 9

IL :

interleukin

IGF-BP2 :

insulin like growth factor-binding protein-2

MCP-1 :

monocyte chemoattractant protein-1

MET-P :

mesenchymal epithelial transition factor-phosphorylated type

HSC :

hepatic stellate cell

SDF-1 :

stromal cell-derived factor-1

VEGF :

vascular endothelial growth factor

NGF :

nerve growth factor

GRO :

growth-related oncogene

OPG :

osteoprotegerin

BECN1 :

beclin-1

CXCR :

CXC-chemokine receptor

ALI :

acute liver injury

ACLF :

acute-on-chronic liver failure

HBV/HCV :

hepatitis B/C virus

AIH :

autoimmune hepatitis

NAFLD :

nonalcoholic fatty liver disease

NASH :

nonalcoholic steatohepatitis

ALD :

alcoholic liver disease

HCC :

hepatocellular carcinoma

D-Gal :

D-galactosamine

α-GalCer :

α-galactosylceramide

NKT :

natural killer T cell

IDO :

indoleamine 2,3-dioxygenase

ALB :

albumin

TBIL :

total bilirubin

PT :

prothrombin time

ALT :

alanine transaminase

INR :

international normalized ratio

CRISPR :

clustered, regularly interspaced, short palindromic repeats

MCD :

methionine-choline-deficient

ECM :

extracellular matrix

LAMP :

lysosome-associated membrane protein

TGF-β1 :

transforming growth factor-beta 1

INF-γ :

interferon γ

HIF-1α :

hypoxia-inducible factor -1α

DLC :

decompensated liver cirrhosis

NPCs :

nonparenchymal cells

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Acknowledgements

The authors thank Prof. Guolin Li from College of Life Sciences, Hunan Normal University and Dr. Jingjing Qu and Prof. Hongcui Cao from The First Affiliated Hospital, Zhejiang University School of Medicine for writing help of this manuscript. Additionally, we would like to thank Editage (http://www.editage.cn) for English language editing.

Funding

This work was supported by the National Key R&D Program of China (2022YFA1105603 and 2022YFC2304405), the National Natural Science Foundation of China (81900563), the Hangzhou Science and Technology Project (20200224), the Independent Task of State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the Fundamental Research Funds for the Central Universities (2022ZFJH003), and CAMS Innovation Fund for Medical Sciences (2019-I2M-5–045).

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Authors and Affiliations

  1. State Key Laboratory for 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, Hangzhou, Zhejiang, 310003, People’s Republic of China

    Lijun Chen, Ning Zhang, Yuqi Huang, Qi Zhang, Yangxin Fang, Jiamin Fu, Yin Yuan, Yifei Li & Charlie Xiang

  2. Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People’s Republic of China

    Lijun Chen, Ning Zhang, Yuqi Huang, Qi Zhang, Yangxin Fang, Jiamin Fu, Yin Yuan, Yifei Li & Charlie Xiang

  3. Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People’s Republic of China

    Lu Chen & Zhenyu Xu

  4. Department of Hematology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310027, People’s Republic of China

    Xin Chen

  5. Jingugaien Woman Life Clinic, Jingu-Gaien 3-39-5 2F, Shibuya-Ku, Tokyo, Japan

    Hiromi Izawa

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  1. Lijun Chen
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Contributions

Charlie Xiang and Lijun Chen designed the manuscript, Lijun Chen wrote the manuscript, Ning Zhang, Yuqi Huang, Qi Zhang, Yangxin Fang, Jiamin Fu, Yin Yuan, Lu Chen, Xin Chen, Zhenyu Xu, Yifei Li, and Hiromi Izawa collected the references and modified the manuscript.

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Correspondence to Charlie Xiang.

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Chen, L., Zhang, N., Huang, Y. et al. Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside. Stem Cell Rev and Rep 19, 2192–2224 (2023). https://doi.org/10.1007/s12015-023-10583-5

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