Z Gastroenterol 2021; 59(01): e52
DOI: 10.1055/s-0040-1722087
Viral Hepatitis, Immunology

TLR4 KO MSC optimized protection in liver IRI via CXCR2/CXCL2-mediated crosstalk with Kupffer cells

C Wang
1   University of Heidelberg, Clinic for Cardiology, Angiology, Pneumology, Heidelberg, Germany
,
P Xu
2   Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Emergency surgery, Wuhan, China
,
G Wang
3   University of Heidelberg, General, Visceral and Transplantation Surgery, Heidelberg, Germany
4   Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Hepatobiliary Surgery, Wuhan, China
,
H Wang
5   Tongji Medical College, Huazhong University of Science and Technology, Department of Genetic Medicine, Wuhan, China
,
Y Zhang
4   Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Hepatobiliary Surgery, Wuhan, China
,
T Billiar
6   University of Pittsburgh, Surgery, Pittsburgh, United States
,
J Zhang
2   Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Emergency surgery, Wuhan, China
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Background Bone marrow-derived mesenchymal stem cells (MSC) ameliorate liver injury caused by ischemia-reperfusion (IR). However, MSC have a short life cycle in applications and difficult homing. Although Toll-like receptor 4 (TLR4) is functionally expressed in MSC, its role in MSC function during liver IR is not clearly defined. Previous studies have found that TLR4 knockout can improve stem cell proliferation, we hypothesize that TLR4 knockout can promote the protective effect of MSC on liver IR

Method MSC isolation from the bone marrow of the Wild-type (WT) mice and TLR4 knockout mice, MSCs were injected 0.5h before live ischemia. After 1h ischemia and 6hrs reperfusion, poor liver reperfusion area, ALT/AST level, cytokines expression and release, polymorphonuclear leukocytes (PMN) recruitment were tested. We also co-culture the MSCs and Liver Non-parenchymal cells (NPC), then give them LPS or H2O2 stimulate to mimic in vivo experiment. Kupffer cells were abolished using liposome to test the Kupffer cells function in this process.

Result We found that TLR4-knockout (KO) MSC infusion during liver IR elicited more protection against ischemia and exhibits less inflammatory cell infiltration than in wild-type (WT) MSC. Kupffer cells induced liver-specific expression of the chemokine CXCL2 during IR, which was markedly enhanced in mice treated with TLR4-KO MSC. Loss of functional TLR4 in MSC markedly enhanced CXCR2 expression. This loss also strengthened MSC crosstalk with Kupffer cells mediated by CXCL2/CXCR2 chemotaxis and recognition, followed by increased IL-10 production in Kupffer cells.

Conclusions TLR4 changes in MSC induce gene expression and functional changes, and these alterations may represent a novel therapeutic strategy to improve the protective capacity of MSC.



Publication History

Article published online:
04 January 2021

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