title: Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs.
abstract: Macrophage colony-stimulating factor (CSF1) is an essential growth and differentiation factor for cells of the macrophage lineage. To explore the role of CSF1 in steady-state control of monocyte production and differentiation and tissue repair, we previously developed a bioactive protein with a longer half-life in circulation by fusing pig CSF1 with the Fc region of pig IgG1a. CSF1-Fc administration to pigs expanded progenitor pools in the marrow and selectively increased monocyte numbers and their expression of the maturation marker CD163. There was a rapid increase in the size of the liver, and extensive proliferation of hepatocytes associated with increased macrophage infiltration. Despite the large influx of macrophages, there was no evidence of liver injury and no increase in circulating liver enzymes. Microarray expression profiling of livers identified increased expression of macrophage markers, i.e., cytokines such as TNF, IL1, and IL6 known to influence hepatocyte proliferation, alongside cell cycle genes. The analysis also revealed selective enrichment of genes associated with portal, as opposed to centrilobular regions, as seen in hepatic regeneration. Combined with earlier data from the mouse, this study supports the existence of a CSF1-dependent feedback loop, linking macrophages of the liver with bone marrow and blood monocytes, to mediate homeostatic control of the size of the liver. The results also provide evidence of safety and efficacy for possible clinical applications of CSF1-Fc.
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Sauter
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Waddell
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Zofia M
authors.initials: ZM
authors.lastname: Lisowski
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Young
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Lucas
authors.initials: L
authors.lastname: Lefevre
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Gemma M
authors.initials: GM
authors.lastname: Davis
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Clohisey
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Mary
authors.initials: M
authors.lastname: McCulloch
authors.affiliation: Agri-Food and Biosciences Institute, Large Park, Hillsborough, Northern Ireland, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Magowan
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Mabbott
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Summers
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Scotland, United Kingdom; and david.hume@roslin.ed.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
mesh_terms: D000818:Animals; D000906:Antibodies; D015703:Antigens, CD; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D009000:Monocytes / Q000502:physiology*; D013552:Swine
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D016173:Macrophage Colony-Stimulating Factor; D003577:Cytochrome P-450 Enzyme System
keywords: CD163; M-CSF; hepatosplenomegaly; hepatostat; macrophages