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Genetic modification by overexpression of target gene in mesenchymal stromal cell for treating liver diseases

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Abstract

Different hepatoxic factors cause irreversible liver injury, leading to liver failure, cirrhosis, and cancer in mammals. Liver transplantation is the only effective strategy, which can improve the prognosis of patients with end-stage liver diseases, but it is limited by liver donor shortage, expensive costs, liver graft rejection and dysfunction, and recurring liver failure. Recently, mesenchymal stromal cells (MSCs) isolated from various tissues are regarded as the main stem cell type with therapeutic effects in liver diseases because of their hepatogenic differentiation, anti-inflammatory, immuoregulatory, anti-apoptotic, antifibrotic, and antitumor capacities. To further improve the therapeutic effects of MSCs, multiple studies showed that genetically engineered MSCs have increased regenerative capacities and are able to more effectively inhibit cell death. Moreover, they are able to secrete therapeutic proteins for attenuating liver injury in liver diseases. In this review, we mainly focus on gene overexpression for reprogramming MSCs to increase their therapeutic effects in treating various liver diseases. We described the potential mechanisms of MSCs with gene overexpression in attenuating liver injury, and we recommend further expansion of experiments to discover more gene targets and optimized gene delivery methods for MSC-based regenerative medicine. We also discussed the potential hurdles in genetic engineering MSCs. In conclusion, we highlight that we need to overcome all scientific hurdles before genetically modified MSC therapy can be translated into clinical practices for patients with liver diseases.

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Abbreviations

LT:

liver transplantation

HT:

hepatocyte transplantation

ESCs:

embryonic stem cells

iPSCs:

induced pluripotent stem cells

HLCs:

hepatocyte-like cells

ALF:

acute liver failure

AFP:

alpha fetoprotein

MSCs:

mesenchymal stromal cells

HCC:

hepatocellular carcinoma

HSC:

hepatic stellate cell

ISCT:

International Society for Cellular Therapy

HGF:

hepatocyte growth factor

FGF:

fibroblast growth factor

EGF:

epidermal growth factor

OSM:

oncostatin M

ALB:

albumin

CK18:

cytokeratin 18

CK19:

cytokeratin 19

bFGF:

basic fibroblast growth factor

IL-1Ra:

interleukin-1-receptor antagonist

IL:

interleukin

MELD:

Model For End-Stage Liver Disease

PE:

plasma exchange

ACLF:

acute-on-chronic liver failure

ALT:

alanine transaminase

miRNA:

microRNA

ZFNs:

zinc finger nucleases

TALENs:

transcription activator-like effector nucleases

HNF4α:

hepatocyte nuclear factor 4 alpha

ICG:

indocyanine green

FOXA2:

forkhead box protein A2

hAAT:

human α1-antitrypsin

CCl4 :

carbon tetrachloride

RSLT:

reduced-size liver transplantation

CXCR4:

C-X-C chemokine receptor type 4

SDF1α:

stromal cell-derived factor 1α

VEGF:

vascular endothelial growth factor

TNF:

tumor necrosis factor

GSH:

glutathione

iNOS:

nitric oxide synthase

HO:

heme oxygenase

Foxp3:

forkhead box P3

PD-L1:

programmed death ligand 1

Th:

T helper

AST:

aspartate transaminase

PDGF:

platelet-derived growth factor

TIMP-1:

tissue inhibitor of metalloprotease-1

TGF:

transforming growth factor

MMP:

matrix metalloprotease

PCNA:

proliferating cell nuclear antigen

EpCAM:

epithelial cell adhesion molecule

HA:

hyaluronic acid

NF-κB:

nuclear factor kappa B

α-SMA:

alpha-smooth muscle actin

IGF-I:

insulin growth factor like-I

IFN:

interferon

sFlt-1:

soluble fms-like tyrosine kinase-1

PEDF:

pigment epithelial-derived factor

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Funding

This work was supported by the National Natural Science Foundation of China (no. 81700553), Zhejiang basic public welfare research program (no. LGF20H030008), and the Independent Fund of State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University.

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  1. Chenxia Hu and Lingfei Zhao contributed equally to this work.

Authors and Affiliations

  1. Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Chenxia Hu & Lanjuan Li

  2. National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China

    Chenxia Hu & Lanjuan Li

  3. Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, Institute of Nephrology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China

    Lingfei Zhao

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  1. Chenxia Hu
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Lanjuan Li contributed to the conception of this study. Chenxia Hu and Lingfei Zhao drafted the manuscript. Chenxia Hu revised the manuscript. All authors read and approved the final manuscript.

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Hu, C., Zhao, L. & Li, L. Genetic modification by overexpression of target gene in mesenchymal stromal cell for treating liver diseases. J Mol Med 99, 179–192 (2021). https://doi.org/10.1007/s00109-020-02031-5

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