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.
Subject(s)
Adiposity/drug effects , Cell Proliferation/drug effects , Fatty Liver/chemically induced , Fetal Growth Retardation/drug therapy , Kupffer Cells/drug effects , Lipid Metabolism/drug effects , Liver/drug effects , Macrophage Colony-Stimulating Factor/pharmacology , Animals , Animals, Newborn , Birth Weight , Cells, Cultured , Dexamethasone , Disease Models, Animal , Fatty Liver/metabolism , Fatty Liver/pathology , Female , Fetal Growth Retardation/chemically induced , Fetal Growth Retardation/metabolism , Fetal Growth Retardation/pathology , Kupffer Cells/metabolism , Kupffer Cells/pathology , Liver/growth & development , Liver/metabolism , Liver/pathology , Macrophage Colony-Stimulating Factor/toxicity , Male , Pregnancy , Rats, Sprague-Dawley , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/agonists , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Signal Transduction/drug effects , Spleen/drug effects , Spleen/metabolism , Spleen/pathology , Sus scrofaABSTRACT
Granulocyte macrophage colony stimulating factor (GM-CSF) is a potent hematopoietic cytokine, which stimulates stem cell proliferation in the bone marrow. We now report that GM-CSF receptors expressed on neural progenitor cells and can mediate a biological response in cells to treat with GM-CSF treated neural progenitor cells exhibited a proliferative response and a marked decrease in terminal differentiation to mature neuron or astrocytes. GM-CSF treatment also suppressed neural progenitor cell apoptosis. These findings suggest that GM-CSF can stimulate the proliferation and inhibit the apoptosis of neural progenitor cells to expand the progenitor population, and that GM-CSF has a potential role in neural development or repair.