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Abstract
Background aimsMacrophages have complex roles in the liver. The aim of this study was to compare profiles of human monocyte-derived macrophages between controls and cirrhotic patients, to determine whether chronic inflammation affects precursor number or the phenotype, with the eventual aim to develop a cell therapy for cirrhosis. MethodsInfusion of human macrophages in a murine liver fibrosis model demonstrated a decrease in markers of liver injury (alanine transaminase, bilirubin, aspartate transaminase) and fibrosis (transforming growth factor-β, α-smooth muscle actin, phosphatidylserine receptor) and an increase in markers of liver regeneration (matrix metalloproteinases [MMP]-9, MMP-12 and TNF-related weak inducer of apoptosis). CD14+ monocytes were then isolated from controls. Monocytes were matured into macrophages for 7 days using a Good Manufacturing Practice–compatible technique. ResultsThere was no significant difference between the mean number of CD14+ monocytes isolated from cirrhotic patients (n = 9) and controls (n = 10); 2.8 ± SEM 0.54 × 108 and 2.5 ± 0.56 × 108, respectively. The mean yield of mature macrophages cultured was also not significantly different between cirrhotic patients and controls (0.9 × 108 ± 0.38 × 108, with more than 90% viability and 0.65 × 108 ± 0.16 × 108, respectively. Maturation to macrophages resulted in up-regulation of a number of genes (MMP-9, CCL2, interleukin [IL]-10 and TNF-related weak inducer of apoptosis). A cytokine and chemokine polymerase chain reaction array, comparing the control and cirrhotic macrophages, revealed no statistically significant differences. ConclusionsMacrophages can be differentiated from cirrhotic patients' apheresis-derived CD14 monocytes and develop the same pro-resolution phenotype as control macrophages, indicating their suitability for clinical therapy.
Highlights
Macrophages are a heterogeneous population of cells with diverse roles within the liver, including phagocytosis, maintaining immune tolerance and both promotion and resolution of inflammation and fibrosis through activation of hepatic stellate cells/ production of cytokines and degradation of the extracellular matrix, respectively [1e4]
CD14þ monocytes were isolated from an apheresis product from a healthy volunteer and matured into macrophages for 7 days in the presence of macrophage colony-stimulating factor (M-CSF) as described in Methods
The livers of mice treated with human macrophages showed significantly reduced fibrosis as measured by Sirius red (P 1⁄4 0.0002) and a trend to reduced myofibroblast activation as measured by alpha-SMA quantification (P 1⁄4 0.59) and expression of the profibrotic gene transforming growth factor (TGF)-b (P 1⁄4 0.13; see Figure 1A)
Summary
Macrophages are a heterogeneous population of cells with diverse roles within the liver, including phagocytosis, maintaining immune tolerance and both promotion and resolution of inflammation and fibrosis through activation of hepatic stellate cells/ production of cytokines and degradation of the extracellular matrix, respectively [1e4] They are involved in the livers’ regenerative response after injury [5,6]. There is currently widespread use of at least four definitions of macrophage activation (M1/M2, alternative/classic activation, “regulatory” macrophages and subdivisions), and there is a requirement for common terminology and consistent use of markers across the literature [10] Macrophages can both promote fibrogenesis by activating the pro-fibrotic cytokine transforming growth factor (TGF)-b [11] and by stimulating myofibroblast proliferation by platelet-derived growth factor (PDGF), IL-1b and tumor necrosis factor-a [12]. Macrophages can be differentiated from cirrhotic patients’ apheresis-derived CD14 monocytes and develop the same pro-resolution phenotype as control macrophages, indicating their suitability for clinical therapy
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