Abstract
Signaling via the colony-stimulating factor 1 receptor (CSF1R) controls the survival, differentiation, and proliferation of macrophages. Mutations in CSF1 or CSF1R in mice and rats have pleiotropic effects on postnatal somatic growth. We tested the possible application of pig CSF1-Fc fusion protein as a therapy for low birth weight (LBW) at term, using a model based on maternal dexamethasone treatment in rats. Neonatal CSF1-Fc treatment did not alter somatic growth and did not increase the blood monocyte count. Instead, there was a substantial increase in the size of liver in both control and LBW rats, and the treatment greatly exacerbated lipid droplet accumulation seen in the dexamethasone LBW model. These effects were reversed upon cessation of treatment. Transcriptional profiling of the livers supported histochemical evidence of a large increase in macrophages with a resident Kupffer cell phenotype and revealed increased expression of many genes implicated in lipid droplet formation. There was no further increase in hepatocyte proliferation over the already high rates in neonatal liver. In conclusion, treatment of neonatal rats with CSF1-Fc caused an increase in liver size and hepatic lipid accumulation, due to Kupffer cell expansion and/or activation rather than hepatocyte proliferation. Increased liver macrophage numbers and expression of endocytic receptors could mitigate defective clearance functions in neonates.NEW & NOTEWORTHY This study is based on extensive studies in mice and pigs of the role of CSF1/CSF1R in macrophage development and postnatal growth. We extended the study to neonatal rats as a possible therapy for low birth weight. Unlike our previous studies in mice and pigs, there was no increase in hepatocyte proliferation and no increase in monocyte numbers. Instead, neonatal rats treated with CSF1 displayed reversible hepatic steatosis and Kupffer cell expansion.
Highlights
Signals initiated following binding of macrophage colonystimulating factor 1 (CSF1) or IL-34 to a shared receptor (CSF1R) control the survival, differentiation, and proliferation of cells of the mononuclear phagocyte lineage [6, 21, 24]
Pig CSF1-Fc is active on rat macrophages but does not affect postnatal growth
Concentrations of CSF1 were found to be higher in fetal than in maternal blood throughout mouse gestation and to peak around the time of birth, at which time there was a peak of CSF1 protein in the liver [41]
Summary
Signals initiated following binding of macrophage colonystimulating factor 1 (CSF1) or IL-34 to a shared receptor (CSF1R) control the survival, differentiation, and proliferation of cells of the mononuclear phagocyte lineage [6, 21, 24]. CSF1-Fc treatment of adult mice produced a rapid increase in the size of the liver associated with extensive hepatocyte proliferation [14]. We considered the possibility that CSF1-Fc might be more efficient in animals with low birth weight (LBW) To this end, we utilized a well-studied model of maternal stress in which pregnant rats are injected with glucocorticoids in the third week of pregnancy [10, 11]. We utilized a well-studied model of maternal stress in which pregnant rats are injected with glucocorticoids in the third week of pregnancy [10, 11] This treatment produces lifelong impacts on several organ systems, notably predisposing to lipid accumulation in the liver [20, 53]. The treatment caused an unexpected, large, but reversible increase in fat deposition in the liver
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