Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs

Macrophage colony-stimulating factor (CSF1) is an essential growth and differentiation factor for cells of the macrophage lineage. To explore the practical applications of CSF1 therapy, we developed a bioactive protein with a longer half-life in circulation by fusing pig CSF1 with Fc region of pig IgG1a. Three consecutive daily doses of CSF1-Fc in 8 week old pigs expanded macrophage populations in blood and organs, accelerated maturation of macrophage populations in peripheral blood monocytes, and expanded progenitor pools in bone marrow. The hepatosplenomegaly present after CSF1-Fc administration was partially due to a substantial increase in macrophage numbers in both organs as well as an increase in proliferating cells in the liver. Despite the large influx of macrophages a panel of biochemical tests to measure liver damage demonstrated normal function in CSF1-Fc treated pigs. Additionally microarray data confirmed that the increase in total liver weight must be primarily due to the extensive proliferation and subsequent increase in hepatocyte numbers. In the current study we have extended our previous finding that CSF1-Fc increased the size of the liver in mice to the domestic pig, an animal that is considerably more human-like in size and vascular biology. CSF1-dependent monocyte recruitment is both necessary and sufficient to drive hepatic proliferation and CSF1-Fc treatment can push it beyond the homeostatic limits even in a large animal. Treatment confirms the existence of a homeostatic feedback loop linking macrophages of the liver with bone marrow and blood monocytes which together regulate the physiological hepatostat as a "macrostat".