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Improvement of mesenchymal stromal cells and their derivatives for treating acute liver failure

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Abstract

After the death of large numbers of cells in liver tissue is triggered by various hepatotoxic factors, intimidating and life-threatening acute liver failure (ALF) can develop with high mortality and expensive costs. Although liver transplantation and hepatocyte transplantation have become substitutes for improving liver regeneration, their applications are inhibited by scarce tissue and cell resources. Therefore, the transplantation of mesenchymal stromal cells (MSCs) and their derivatives including hepatocyte-like cells (HLCs), conditioned medium (CM), and exosomes (Ex) can help alleviate liver injury in ALF individuals or animal models via engraftment into liver tissue, hepatogenic differentiation, the promotion of host hepatocyte proliferation, the secretion of anti-inflammatory factors and antioxidants, and the enhancement of liver regeneration in vivo. In addition, biomaterial scaffolds protect MSCs against a harsh microenvironment in vitro and in vivo, in addition to providing physical and directional support for liver regeneration. In this review, we aimed to discuss the underlying mechanisms and therapeutic effects of MSCs and their derivatives on rescuing ALF animal models according to current studies. Further breakthroughs are required to establish safer, more stable, and more effective stem cell–based therapy in regenerative medicine for repairing liver injury, thus reducing the morbidity and mortality of ALF in the near future.

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Abbreviations

ALF:

Acute liver failure

MSC:

Mesenchymal stromal cell

iPSCs:

Induced pluripotent stem cells

ESCs:

Embryonic stem cells

HLCs:

Hepatocyte-like cells

CCl4 :

Carbon tetrachloride

CM:

Conditioned medium

Ex:

Exosomes

HE:

Hepatic encephalopathy

INR:

International normalized ratio

ACLF:

Acute-on-chronic liver failure

APAP:

Acetaminophen

NKT:

Natural killer T

NK:

Natural killer

IFN-γ:

Interferon-gamma

TNF-α:

Tumor necrosis factor alpha

ConA:

Concanavalin A

α-GalCer:

Alpha-galactosylceramide

LPS:

Lipopolysaccharide

DCs:

Dendritic cells

Tregs:

T regulatory cells

TLR4:

Toll-like receptor 4

PMNs:

Polymorphonuclear neutrophils

IDO:

Indoleamine 2,3-dioxygenase

TGF:

Transforming growth factor

PGE2:

Prostaglandin E2

ATP:

Adenosine triphosphate

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

TBIL:

Total bilirubin

HO-1:

Heme oxygenase-1

AFP:

Alpha fetal protein

CK:

Cytokeratin

VEGF:

Vascular endothelial growth factor

HMGB1:

High mobility group box 1 protein

EpCAM:

Epithelial cell adhesion molecule

GSH:

Glutathione

Nrf2:

NF-E2-related factor 2

SOD:

Superoxide dismutase

HGF:

Hepatocyte growth factor

UCMSCs:

Umbilical cord–derived MSCs

IL-1Ra:

IL-1 receptor antagonist

BMMSCs:

Bone marrow–derived MSCs

ConA:

Concanavalin A

UCB-MSCs:

Umbilical cord blood–derived MSCs

ADMSCs:

Adipose-derived MSCs

iPSC-MSCs:

iPSC-derived MSCs

PCNA:

Proliferating cell nuclear antigen

SDF:

Stromal-derived factor

CXCR4:

Chemokine CXC receptor 4

ZD:

Zeaxanthin dipalmitate

H2O2 :

Hydrogen dioxide

miR-210:

MicroRNA-210

CAT:

Catalase

AF-MSCs:

Amniotic fluid–derived MSCs

HPL:

Hepatic progenitor-like

STAT3:

Signal transducer and activator of transcription 3

NKTregs:

Natural killer T regulatory cells

NKT17:

IL-17-producing natural killer T

MSC-H-CM:

CM derived from MSCs cocultured with hepatocytes

D-GalN:

D-galactosamine

H-CM:

CM derived from hepatocytes

NCM:

Nonconditioned medium

TAA:

Thioacetamide

ICAM:

Intercellular cell adhesion molecule

GPX1:

Glutathione peroxidase-1

PG:

Prostaglandin

PLGA:

Poly (lactic acid-glycolic acid)

RSF:

Regenerated silk fibroin

LADs:

Liver assist devices

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81700553), the China Postdoctoral Science Foundation (No. 2017 M183789), the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (No. 81121002), and the Independent Fund of State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University.

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

    Chenxia Hu & Lanjuan Li

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Hu, C., Li, L. Improvement of mesenchymal stromal cells and their derivatives for treating acute liver failure. J Mol Med 97, 1065–1084 (2019). https://doi.org/10.1007/s00109-019-01804-x

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