Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/srep35146
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- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Keio University Medical Fund
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The fundamental mechanism how heterogeneous hepatic macrophage (M phi) subsets fulfill diverse functions in health and disease has not been elucidated. We recently reported that CCR9(+) inflammatory M phi s play a critical role in the course of acute liver injury. To clarify the origin and differentiation of CCR9(+)M phi s, we used a unique partial bone marrow (BM) chimera model with liver shielding for maintaining hepatic resident M phi s. First, irradiated mice developed less liver injury with less M phi s accumulation by Concanavalin A (Con A) regardless of liver shielding. In mice receiving further BM transplantation, CD11b(low)F4/80(high) hepatic-resident M phi s were not replaced by transplanted donors under steady state, while under inflammatory state by Con A, CCR9(+)M phi s were firmly replaced by donors, indicating that CCR9(+)M phi s originate from BM, but not from hepatic-resident cells. Regarding the mechanism of differentiation and proliferation, EdU(+)CCR9(+)M phi s with a proliferative potential were detected specifically in the inflamed liver, and in vitro study revealed that BM-derived CD11b(+) cells co-cultured with hepatic stellate cells (HSCs) or stimulated with retinoic acids could acquire CCR9 with antigen-presenting ability. Collectively, our study demonstrates that inflammatory M phi s originate from BM and became locally differentiated and proliferated by interaction with HSCs via CCR9 axis during acute liver injury.
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