Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction (MI) and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell type in terms of their origins and functional effects in vivo. Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen-inducible Cre for cellular lineage-tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Lineage tracing with four additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after MI. Periostin-traced myofibroblasts also revert back to a less-activated state upon injury resolution. Our results define the myofibroblast as a periostin-expressing cell type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts.
Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.
Obesity and adiponectin depletion have been associated with the occurrence of nonalcoholic fatty liver disease (NAFLD). The goal of this study was to identify the relationship between weight gain, adiponectin signaling, and development of nonalcoholic steatohepatitis (NASH) in an obese, diabetic mouse model. Leptin-receptor deficient (Leprdb/db) and C57BL/6 mice were administered a diet high in unsaturated fat (HF) (61%) or normal chow for 5 or 10 weeks. Liver histology was evaluated using steatosis, inflammation, and ballooning scores. Serum, adipose tissue, and liver were analyzed for changes in metabolic parameters, messenger RNA (mRNA), and protein levels. Leprdb/db HF mice developed marked obesity, hepatic steatosis, and more than 50% progressed to NASH at each timepoint. Serum adiponectin level demonstrated a strong inverse relationship with body mass (r = −0.82; P < 0.0001) and adiponectin level was an independent predictor of NASH (13.6 μg/mL; P < 0.05; area under the receiver operating curve (AUROC) = 0.84). White adipose tissue of NASH mice was characterized by increased expression of genes linked to oxidative stress, macrophage infiltration, reduced adiponectin, and impaired lipid metabolism. HF lepr db/db NASH mice exhibited diminished hepatic adiponectin signaling evidenced by reduced levels of adiponectin receptor-2, inactivation of adenosine monophosphate activated protein kinase (AMPK), and decreased expression of genes involved in mitochondrial biogenesis and β-oxidation (Cox4, Nrf1, Pgc1α, Pgc1β and Tfam). In contrast, recombinant adiponectin administration up-regulated the expression of mitochondrial genes in AML-12 hepatocytes, with or without lipid-loading. Conclusion Leprdb/db mice fed a diet high in unsaturated fat develop weight gain and NASH through adiponectin depletion, which is associated with adipose tissue inflammation and hepatic mitochondrial dysfunction. We propose that this murine model of NASH may provide novel insights into the mechanism for development of human NASH.
MM, Kowdley KV. Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice. Am J Physiol Gastrointest Liver Physiol 310: G117-G127, 2016. First published November 12, 2015; doi:10.1152/ajpgi.00246.2015.-The aim of this study was to determine the effect of iron overload in the development of nonalcoholic steatohepatitis (NASH) in a genetically obese mouse model (Lepr db/db ). Leptin receptor-deficient mice were fed a normal or an iron-supplemented chow for 8 wk and switched to normal chow for 8 wk. All dietary iron (DI)-fed mice developed hepatic iron overload predominantly in the reticuloendothelial system. Hepatocellular ballooning injury was observed in the livers of 85% of DI mice, relative to 20% of chow-fed Lepr db/db . Hepatic malonyldialdehyde levels and mRNA levels of antioxidant genes (Nrf2, Gpx1, and Hmox1) were significantly increased in the DI mice. Hepatic mRNA levels of mitochondrial biogenesis regulators Pgc1␣, Tfam, Cox4, and Nrf1 were diminished in the DI mice. In addition, gene expression levels of cytokines (Il6, Tnf␣) and several innate and adaptive immune cell markers such as Tlr4, Inos, CD11c, CD4, CD8, and Ifn␥ were significantly increased in livers of the DI group. Strikingly, Nlrp3, a component of the inflammasome and Il18, a cytokine elicited by inflammasome activation, were significantly upregulated in the livers of DI mice. In addition, RAW 264.7 macrophages loaded with exogenous iron showed significantly higher levels of inflammatory markers (Inos, Tnf␣, Mcp1, Tlr4). Thus dietary iron excess leads to hepatic oxidative stress, inflammasome activation, induction of inflammatory and immune mediators, hepatocellular ballooning injury, and therefore NASH in this model. Taken together, these studies indicate a multifactorial role for iron overload in the pathogenesis of NASH in the setting of obesity and metabolic syndrome. iron excess; hepatocellular ballooning; inflammasome; immune cell activation; reticuloendothelial system NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is the most prevalent chronic liver disease in the world and is strongly associated with obesity and the attendant metabolic syndrome (17
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