With increased levels of fractalkine lend support to this potential mechanism of fibrosis reduction

Its receptor CX3CR1 leads to differentiation of macrophages having an anti-inflammatory phenotype and prolongs their survival leading to reduced fibrosis. Our findings showing elevated IL-10 mRNA expression characteristic of alternately activated macrophages in livers of hAEC treated. The importance of macrophage plasticity in wound healing and hepatic tissue regeneration is increasingly recognised since alternatively activated M2 macrophages are thought to contribute to wound healing by secreting anti-inflammatory cytokines and collagen degrading enzymes. Given the changes in F4/80 positive macrophage numbers and fibrosis with hAEC treatment, we explored whether the macrophage population displayed a phenotype consistent with wound healing and tissue remodelling. M2 macrophages express several distinct genes including YM-1, Cadm-1, CD206, CD36 and Cnrip-1. Analysis of hepatic mRNA expression showed that YM-1 mRNA, a chitinase family member, the anti-inflammatory cytokine IL10 and the mannose receptor CD206 produced by alternatively activated macrophages, were significantly increased in CCl4- treated mice following hAEC transplantation compared to control animals given CCl4 alone. A decrease in the ratio of IL-12b to IL-10 expression further supports skewing towards a M2 phenotype. In addition, macrophages are an important source of matrix degrading enzymes. Liver from hAEC treated mice demonstrated significantly greater expression of MMP-9, which effectively degrades collagen, and significantly less MMP12, which has been reported to inhibit the production of MMP9 and increase hepatic fibrosis. These are important new findings as there are few reports BAY-60-7550 describing the effects of exogenous stem cells on macrophage phenotype. Mesenchymal stem cells have very recently been shown to regulate the switching of macrophages to a M2 phenotype in a murine model of myocardial infarction and multipotent adult progenitor cells to induce a beneficial shift from M1 to M2 in a rat model of spinal cord injury. Recently a therapeutic avenue using M2 macrophages has been suggested as CCl4- treated mice infused with alternatively activated macrophages showed reduced hepatic fibrosis. Therefore, it will be important to determine the influence of exogenous stem cells on hepatic macrophages in the setting of liver injury. In summary, these findings suggest that hAEC induce changes to macrophage recruitment and promote a wound-healing phenotype that is associated with amelioration of hepatic fibrosis. Our results offer novel insights into potential mechanisms underlying the resolution of established hepatic fibrosis induced by exogenously delivered stem-like cells derived from the human placenta. The escalating obesity trend in man is due to an imbalance between energy intake and energy expenditure. Energy intake is influenced by the effect of food’s energy density, total energy content and meal frequency and the extent to which these alter satiety. Of these factors, meal frequency has received least attention.