The number of individuals aged 65 or older is projected to increase globally from 524 million in 2010 to nearly 1. 5 billion in 2050. Aged individuals are particularly at risk for developing chronic ...illness, while being less able to regenerate healthy tissue and tolerate whole organ transplantation procedures. In the liver, these age-related diseases include non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis, fibrosis, and cirrhosis. Hepatic macrophages, a population comprised of both Kupffer cells and infiltrating monocyte derived macrophages, are implicated in several chronic liver diseases and also play important roles in the homeostatic functions of the liver. The effects of aging on hepatic macrophage population dynamics, polarization, and function are not well understood. Studies performed on macrophages derived from other aged sources, such as the bone marrow, peritoneal cavity, lungs, and brain, demonstrate general reductions in autophagy and phagocytosis, dysfunction in cytokine signaling, and altered morphology and distribution, likely mediated by epigenetic changes and mitochondrial defects, that may be applicable to hepatic macrophages. This review highlights recent findings in macrophage developmental biology and function, particularly in the liver, and discusses the role of macrophages in various age-related liver diseases. A better understanding of the biology of aging that influences hepatic macrophages and thus the progression of chronic liver disease will be crucial in order to develop new interventions and treatments for liver disease in aging populations.
The mechanisms by which steatosis of the liver progresses to non-alcoholic steatohepatitis and end-stage liver disease remain elusive. Metabolic derangements in hepatocytes controlled by SIRT1 play a ...role in the development of fatty liver in inbred animals. The ability to perform similar studies using human tissue has been limited by the genetic variability in man. We generated human induced pluripotent stem cells (iPSCs) with controllable expression of SIRT1. By differentiating edited iPSCs into hepatocytes and knocking down SIRT1, we found increased fatty acid biosynthesis that exacerbates fat accumulation. To model human fatty livers, we repopulated decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1 knockdown iPSC-derived hepatocytes and found that the human iPSC-derived liver tissue developed macrosteatosis, acquired proinflammatory phenotype, and shared a similar lipid and metabolic profiling to human fatty livers. Biofabrication of genetically edited human liver tissue may become an important tool for investigating human liver biology and disease.
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•Edited human iPSCs can control SIRT1 expression•Low SIRT1 expression in human iPSC hepatocytes increases fatty acid biosynthesis•Human iPSC-derived livers developed macrosteatosis and inflammatory phenotype•Metabolic profile in human iPSC-derived fatty livers is similar to human NASH livers
Collin de l’Hortet et al. biofabricated human fatty livers using genetically modified human hepatocytes differentiated from induced pluripotent stem cells, mesenchymal cells, fibroblasts, and macrophages. This methodology uncovered the molecular mechanisms of downregulated SIRT1 in human liver tissue. The biofabricated tissue reflected many aspects of human livers with non-alcoholic fatty liver disease.
Exposure of mice to a diet containing 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) induces porphyrin accumulation, cholestasis, immune response, and hepatobiliary damage mimicking hepatic ...porphyria and sclerosing cholangitis. Although β-catenin signaling promotes hepatocyte proliferation, and macrophages are a source of Wnts, the role of macrophage-derived Wnts in modulating hepatobiliary injury/repair remains unresolved. We investigated the effect of macrophage-specific deletion of Wntless, a cargo protein critical for cellular Wnt secretion, by feeding macrophage-Wntless-knockout (Mac-KO) and wild-type littermates a DDC diet for 14 days. DDC exposure induced Wnt11 up-regulation in macrophages. Mac-KO mice on DDC showed increased serum alkaline phosphatase, aspartate aminotransferase, direct bilirubin, and histologic evidence of more cell death, inflammation, and ductular reaction. There was impaired hepatocyte proliferation evidenced by Ki-67 immunostaining, which was associated with decreased hepatocyte β-catenin activation and cyclin-D1 in Mac-KO. Mac-KO also showed increased CD45, F4/80, and neutrophil infiltration after DDC diet, along with increased expression of several proinflammatory cytokines and chemokines. Gene expression analyses of bone marrow–derived macrophages from Mac-KO mice and F4/80+ macrophages isolated from DDC-fed Mac-KO livers showed proinflammatory M1 polarization. In conclusion, this study shows that a lack of macrophage Wnt secretion leads to more DDC-induced hepatic injury due to impaired hepatocyte proliferation and increased M1 macrophages, which promotes immune-mediated cell injury.
Cumulative evidence has indicated that mitochondrial respiration dysfunction plays important roles in tumorigenesis. However, the role of COX7RP, a critical regulator in the formation of ...mitochondrial respiratory supercomplex that has been suggested to be over-expressed in hepatocellular carcinoma (HCC) by our bioinformatic analysis of TCGA data, in tumor progression remains largely unclear. In this study, we found that COX7RP is frequently over-expressed in HCC mainly due to the down-regulation of miR-130a-3p and predicts poor prognosis of HCC patients. Functional experiments revealed that COX7RP promoted both growth and metastasis of HCC through induction of cell cycle progression and epithelial to mesenchymal transition (EMT), and suppression of cell apoptosis. Mechanistically, increased generation of reactive oxygen species (ROS) and subsequently activated nuclear transcription factor-κB (NF-κB) signaling was found to contribute to the promotion of HCC cell growth and metastasis by COX7RP. Collectively, COX7RP plays a critical oncogenic role in hepatocellular carcinogenesis, supporting COX7RP as a novel prognostic factor and therapeutic target in HCC.
Maternal hypercholesterolemia has been implicated in earlier onset of atherosclerotic lesions in neonatal offspring. In this study, we investigated whether maternal exposure to soy protein isolate ...(SPI) diet attenuated the progression of atherosclerosis in F1 offspring.
Pregnant apolipoprotein E knockout (Apoe−/−) female mice were fed SPI diet until postnatal day 21 (PND21) of the offspring (SPI-offspring). SPI-offspring were switched at PND21 to casein (CAS) diet until PND140. Mice fed CAS throughout their lifetime (gestation to adulthood) were used as controls (CAS-offspring).
Atherosclerotic lesions in the aortic sinuses were reduced in SPI-offspring compared with CAS-offspring. Total serum cholesterol levels in CAS-offspring or dams were comparable to levels in their SPI-counterparts, suggesting that alternative mechanisms contributed to the athero-protective effect of maternal SPI diet. Aortic VCAM-1, MCP-1, and TNF-α mRNA and protein expression, and expression of macrophage pro-inflammatory cytokines was reduced in SPI-offspring. Interestingly, CD4+ T cells from SPI-offspring showed reduced IFN-γ expression (Th1), while the expression of IL-10 (Th2/Treg), and IL-13 (Th2) was increased. DNA methylation analyses revealed that anti-inflammatory T cell-associated Gata3 and Il13 promoter regions were hypomethylated in SPI-offspring. These findings suggest that anti-inflammatory macrophage and T cell response may have contributed to the athero-protective effect in SPI-offspring.
Our findings demonstrate that gestational and lactational soy diet exposure inhibits susceptibility to atherosclerotic lesion formation by promoting anti-inflammatory responses by macrophages and T cells.
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•Maternal hypercholesterolemia has been implicated in earlier onset of atherosclerotic lesions in neonatal offspring.•We investigated if prenatal exposure to soy diet attenuates the development of atherosclerosis in F1 offspring.•While maternal soy protein isolate (SPI) diet did not affect total cholesterol, it did reduce atherosclerotic lesions in SPI-offspring.•VCAM-1, MCP-1, and TNF-alpha expression is reduced in SPI-offspring.•In SPI-offspring, expression of anti-inflammatory cytokines by T cells was increased.
Modified LDL uptake by macrophages lead to formation of foam cells is an early event in atherosclerosis. Recent studies have suggested that macrophage polarization contributes to the progression of ...atherosclerosis. In this report, we investigated the hypothesis that macrophage polarization differentially affects modified LDL uptake and subsequent foam cell formation. Bone marrow-derived macrophages (BMDM) were exposed to LPS and IFNγ or IL-4 to induce M1 and M2 macrophage polarization. The formation of foam cells was assessed after exposing M1 and M2 macrophages to oxidized-LDL. Our results show that formation of foam cells was slightly increased in M2 macrophages. Interestingly, accumulation of neutral lipids was high in M1 macrophages indicating M1 polarization promotes foam cells. In M1 macrophages, mRNA and protein expression of scavenger receptor CD36 was lower compared to unpolarized macrophages. Notably, mRNA and protein expression of LOX-1 were increased several fold in M1 macrophages. M2 polarized BMDM from CD36 knock out or scavenger receptor-A (SR-A) knockout mice showed reduced foam cells. Surprisingly, M1 polarized macrophages from CD36 or SR-A knockout mice showed similar levels of foam cells compared to M1 polarized macrophages from wild type mice. These results suggest that CD36 and SR-A do not contribute to increased foam cells in M1 macrophages. Further studies also reveal that NF-kB activation through TLR4 is the major contributor for increased LOX1-expression and foam cell formation in M1 polarized macrophages. Macrophage plasticity, specifically polarization of macrophages to pro-inflammatory M1 phenotype promotes foam cell formation through LOX-1, which has implications for the progression of atherosclerotic plaques.
Atherosclerosis is a chronic inflammatory disease, and recent studies have shown that infection at remote sites can contribute to the progression of atherosclerosis in hyperlipidemic mouse models. In ...this report, we tested the hypothesis that genital Chlamydia infection could accelerate the onset and progression of atherosclerosis.
Apolipoprotein E (Apoe−/−) and LDL receptor knockout (Ldlr−/−) mice on a high-fat diet were infected intra-vaginally with Chlamydia muridarum. Atherosclerotic lesions on the aortic sinuses and in the descending aorta were assessed at 8-weeks post-infection. Systemic, macrophage, and vascular site inflammatory responses were assessed and quantified.
Compared to the uninfected groups, infected Apoe−/− and Ldlr−/− mice developed significantly more atherosclerotic lesions in the aortic sinus and in the descending aorta. Increased lesions were associated with higher circulating levels of serum amyloid A-1, IL-1β, TNF-α, and increased VCAM-1 expression in the aortic sinus, suggesting an association with inflammatory responses observed during C. muridarum infection. Genital infection courses were similar in Apoe−/−, Ldlr−/−, and wild type mice. Further, Apoe−/− mice developed severe uterine pathology with increased dilatations. Apoe-deficiency also augmented cytokine/chemokine response in C. muridarum infected macrophages, suggesting that the difference in macrophage response could have contributed to the genital pathology in Apoe−/− mice.
Overall, these studies demonstrate that genital Chlamydia infection exacerbates atherosclerotic lesions in hyperlipidemic mouse and suggest a novel role for Apoe in full recovery of uterine anatomy after chlamydial infection.
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•Genital Chlamydia infection exacerbated atherosclerosis in two independent hyperlipidemic mouse models of atherosclerosis.•Chlamydia infection increased pro-inflammatory cytokines, chemokines, and VCAM-1 expression.•Interestingly, Chlamydia infection showed uterine pathology only in apoE-deficient mice.
Directed differentiation of hepatocytes from induced pluripotent stem cells (iPSCs) holds promise as source material for treating some liver disorders. The unlimited availability of perfectly ...differentiated iPSC-derived hepatocytes will dramatically facilitate cell therapies. While
systems to manufacture large quantities of iPSC-derived cells have been developed, we have been unable to generate and maintain stable and mature adult liver cells ex vivo. This short review highlights important challenges and possible solutions to the current state of hepatocyte biofabrication
for cellular therapies to treat liver diseases. Successful cell transplantation will require optimizing the best cell function, overcoming limitations to cell numbers and safety, as well as a number of other challenges. Collaboration among scientists, clinicians, and industry is critical for
generating new autologous stem cell-based therapies to treat liver diseases.
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