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Treatment of cytokine release syndrome-induced vascular endothelial injury using mesenchymal stem cells

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Abstract

Cytokine release syndrome (CRS) is an acute systemic inflammatory reaction in which hyperactivated immune cells suddenly release a large amount of cytokines, leading to exaggerated inflammatory responses, multiple organ dysfunction, and even death. Although palliative treatment strategies have significantly reduced the overall mortality, novel targeted treatment regimens with superior therapy efficacy are urgently needed. Vascular endothelial cells (ECs) are important target cells of systemic inflammation, and their destruction is considered to be the initiating event underlying many serious complications of CRS. Mesenchymal stem/stromal cells (MSCs) are multipotent cells with self-renewing differentiation capacity and immunomodulatory properties. MSC transplantation can effectively suppress the activation of immune cells, reduce the bulk release of cytokines, and repair damaged tissues and organs. Here, we review the molecular mechanisms underlying CRS-induced vascular endothelial injury and discuss potential treatments using MSCs. Preclinical studies demonstrate that MSC therapy can effectively repair endothelium damage and thus reduce the incidence and severity of ensuing CRS-induced complications. This review highlights the therapeutic role of MSCs in fighting against CRS-induced EC damage, and summarizes the possible therapeutic formulations of MSCs for improved efficacy in future clinical trials.

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Abbreviations

CAR-T:

Chimeric antigen receptor T-cell

CCN1:

CCN family member 1

CD33:

Cluster of differentiation 33

COVID-19:

The coronavirus disease 2019

CRS:

Cytokine release syndrome

CXC:

C-X-C motif chemokine

CXCR:

CXC receptor

CYR61:

Cysteine-rich angiogenic inducer 61

EC:

Endothelial cells

HGF:

Hepatocyte growth factor

HLA-DR:

Human leukocyte antigen—DR isotype

HLH:

Hemophagocytic lymphohistiocytosis

HO-1:

Heme oxidase-1

HUVEC:

Human umbilical vascular endothelial cell

IDO:

Indoleamine 2,3-dioxygenase

IFN-γ:

Interferon-γ

IL-2:

Interleukin-2

IL-6R:

IL-6 receptor

MAPK:

Mitogen-activated protein kinase

MAS:

Macrophage activation syndrome

MCP-1:

Monocyte chemoattractant protein-1

MIP-1α:

Macrophage inflammatory protein-1α

MRTF-A:

Myocardin-related transcription factor-A

MSC:

Mesenchymal stem cell

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor κB

NK:

Natural killer

NQO1:

NADPH-dependent quinone oxidoreductase

PI3K/Akt:

Phosphoinositide-3-kinase–protein kinase B/Akt

ROCK:

Rho-associated kinases

ROS:

Reactive oxygen species

SDF:

Stromal cell-derived factor

TLS:

Tumor lysis syndrome

TNF-α:

Tumor necrosis factor-α

TSG-6:

TNF-stimulated gene 6

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgements

We thank Medjaden Inc. for scientific editing of this manuscript. We thank Figdraw (www.figdraw.com) for its help in creating the figures.

Funding

This study was supported by the National Key Research and Development Program of China (2022YFA1105600), Science and Technology Project of Wuhan (No: 2020020602012112), Haihe Laboratory of Cell Ecosystem Innovation Fund (HH22KYZX0046), and the Tianjin Free Trade Zone Innovation Development Project 211 (ZMCY-03-2021002-01) funded the study. We are also grateful for the support from the 3551 Talent Plan of China Optics Valley.

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Authors and Affiliations

  1. Department of Laboratory Medicine, The First Affiliated Hospital of Yangtze University, Jingzhou, China

    Yuyan Wang & Wen Fan

  2. Health Science Center, Yangtze University, Jingzhou, China

    Yuyan Wang

  3. Wuhan Optics Valley Vcanbiopharma Co., Ltd, Wuhan, China

    Haibo Dong, Tengyun Dong, Lulu Zhao, Yu Zhang & Weiqi Yao

  4. Key Industrial Base for Stem Cell Engineering Products, Tianjin, China

    Haibo Dong, Tengyun Dong, Lulu Zhao, Yu Zhang & Weiqi Yao

  5. Haihe Laboratory of Cell Ecosystem, Tianjin, China

    Yu Zhang

  6. Department of Biology and Medicine, Hubei University of Technology, Wuhan, China

    Weiqi Yao

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YW performed literature reviewing and wrote the first draft of the manuscript. HD, TD, and LZ contributed partial literature study and discussion. WF, YZ, and WQ revised the manuscript. All authors read and approved the final manuscript.

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Wang, Y., Dong, H., Dong, T. et al. Treatment of cytokine release syndrome-induced vascular endothelial injury using mesenchymal stem cells. Mol Cell Biochem (2023). https://doi.org/10.1007/s11010-023-04785-1

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