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.
