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Human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease by inhibiting ERK phosphorylation in neutrophils

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Abstract

Inflammatory bowel disease (IBD) can be caused by a variety of factors, including hereditary and environmental influences, that lead to dysfunction of the intestinal immune system. Mesenchymal stem cells (MSCs) exhibit important regulatory roles in relieving inflammation and repairing damaged tissues. Although neutrophils are important participants in the development of inflammatory reactions, they are also essential for maintaining intestinal balance during the process of mitigation of IBD by MSCs. Here, we constructed a dextran sulfate sodium (DSS)-induced mouse IBD model and evaluated the effects of treatment with human umbilical cord MSCs. Mouse body weight, faecal traits, colon/spleen gross morphology, tissue histology and immunohistochemical staining, and inflammatory factors were analysed. Magnetic beads were used to sort infiltrating neutrophils from intestinal tissues, and their phenotypes were identified. The neutrophil inflammatory environment was also simulated in vitro, and signalling pathways involved in MSC regulation of neutrophil phenotype were analysed. Human umbilical cord MSCs effectively alleviated DSS-induced weight loss, colon shortening, and intestinal mucosal injury, and reduced clinical disease activity index. The number of neutrophils that infiltrated the intestines of mice treated with human umbilical cord MSCs were decreased and polarised toward the N2 phenotype; at the same time, ERK phosphorylation was inhibited. In vitro experiments showed that addition of the ERK phosphorylation inhibitor, PD98059, down-regulated the expression of N1 neutrophils, while up-regulating that of N2 neutrophils. The colon tissues from patients with IBD were infiltrated with neutrophils. Further, relative to healthy controls, the markers of N1 neutrophils (ICAM-1, FAS, and CCL3) were highly expressed in colon tissues from patients with IBD, whereas the markers of N2 neutrophils (VEGF, CCL2, and CXCR4) were almost undetectable. In conclusion, during alleviation of IBD, human umbilical cord MSCs polarise neutrophils toward the “N2” phenotype by inhibiting activation of ERK signalling.

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Abbreviations

CD:

Crohn’s disease

CXCR4:

CXC chemokine receptor 4

DAI:

Disease activity index

DSS:

Dextran sodium sulfate

FAS:

Factor-associated suicide

FCM:

Flow cytometry

HE:

Haematoxylin–eosin

IBD:

Inflammatory bowel disease

ICAM-1:

Intercellular cell adhesion molecule-1

IHC:

Immunohistochemistry analysis

IL:

Interleukin

LPS:

Lipopolysaccharide

MACS:

Magnetic-activated cell sorting

MCP1/CCL2:

Low expression of monocyte chemotactic protein 1

MIP-1α/CCL3:

Giant phage cell inflammatory protein-1α

MSC:

Mesenchymal stem cell

QRT-PCR:

Quantitative real-time polymerase chain reaction

TNF:

Tumour necrosis factor

UC:

Ulcerative colitis

VEGF:

Vascular endothelial growth factor

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (Grant Nos. 81670502, 81672416 and 81602883), Jiangsu Key Research and Development Project (Grant No. BE2016717), the Scientific Research Foundation of Jiangsu University (Grant No. FCJJ2015023), the opening project of the Key Laboratory of Embryo Molecular Biology, Ministry of Health of China, and Shanghai Key Laboratory of Embryo and Reproduction Engineering (Grant No. KF201601), Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions and Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application (Grant No. SS2018003).

Funding

The National Natural Science Foundation of China (Grant No. 81670502).

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Author notes

  1. Gaoying Wang and Mbobda Defo Marius Joel have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People’s Republic of China

    Gaoying Wang, Mbobda Defo Marius Joel, Jingyan Wang, Xiu Cai, Dickson Kofi Wiredu Ocansey, Yongmin Yan, Hui Qian, Xu Zhang, Wenrong Xu & Fei Mao

  2. The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, 212300, Jiangsu, People’s Republic of China

    Jintao Yuan

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Contributions

GW, conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; MDMJ, collection and/or assembly of data and data analysis; JY, conception and design, collection of data, data analysis and interpretation; JW, collection and/or assembly of data and data analysis; XC, data analysis and interpretation; DKWO, collection and/or assembly of data and data analysis; YY, provision of study material and interpretation; HQ, data analysis and interpretation; XZ, collection and/or assembly of data; WX, data analysis and interpretation; FM, study design, data analysis and interpretation, manuscript writing, and final approval of manuscript. All authors read and approved the final manuscript.

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Correspondence to Fei Mao.

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Wang, G., Joel, M.D.M., Yuan, J. et al. Human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease by inhibiting ERK phosphorylation in neutrophils. Inflammopharmacol 28, 603–616 (2020). https://doi.org/10.1007/s10787-019-00683-5

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