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Am J Pathol [journal]
- Hepatocytes, Rather than Cholangiocytes, Can Be the Major Source of Primitive Ductules in the Chronically Injured Mouse Liver. [JOURNAL ARTICLE]
- Am J Pathol 2014 Mar 1.
The proliferation of biliary lineage cells in chronic liver diseases, which leads to formation of primitive ductules in portal areas of the hepatic lobule, may be important not only for liver regeneration, but also for initiation of liver cancer. Thus, understanding how these primitive ductular cells emerge and proliferate in chronically injured liver holds promise for development of therapeutic strategies for liver diseases. However, the origin of these primitive ductular cells remains controversial. We used genetic lineage tracing to determine the origin of cells that form primitive ductules in a mouse model of chronic liver injury. Hepatocytes, rather than cholangiocytes, were the major source of cells for the primitive ductules formed in response to chronic liver damage. Moreover, our results indicate that activation of the Notch-Hes1 signaling axis is significant for conversion of hepatocytes into primitive ductular cells in chronically injured liver. These findings should be valuable in elucidating the mechanism of liver regeneration associated with the fate-conversion of hepatocytes and in developing therapeutic strategies for liver diseases.
- Protein Profiling of H. pylori-Associated Gastric Cancer. [JOURNAL ARTICLE]
- Am J Pathol 2014 Feb 28.
Helicobacter pylori infection is an initiating factor in the development of gastric cancer. Gastric cancer can be divided into two groups on the basis of H. pylori serological status; seropositive H. pylori status predicts favorable prognosis in patients with gastric cancer. By using the protein pathway array, we identified 20 differentially expressed proteins in primary gastric cancer tissues between the H. pylori-seropositive and H. pylori-seronegative groups. Our results indicate that both BAK1 and calpastatin are favorable prognostic factors in H. pylori-seropositive gastric cancer patients. In contrast, DACH1 is a favorable prognostic factor in H. pylori-seronegative gastric cancer patients. Different signaling pathways were found to be altered between H. pylori-seropositive and H. pylori-seronegative gastric cancer, which may account for the different tumorigenesis and outcomes between these two subsets of patients.
- CD133-Targeted Niche-Dependent Therapy in Cancer: A Multipronged Approach. [JOURNAL ARTICLE]
- Am J Pathol 2014 Feb 28.
Cancer treatment continues to be challenged by the development of therapeutic resistances and relapses in the clinical setting, which are largely attributed to tumor heterogeneity, particularly the existence of cancer stem cells (CSCs). Thus, targeting the CSC subpopulation may represent an effective therapeutic strategy. However, despite advances in identifying and characterizing CD133(+) CSCs in various human cancers, efforts to translate these experimental findings to clinical modalities have been slow in the making, especially in light of the growing awareness of CSC plasticity and the foreseeable pitfall of therapeutically targeting CSC base sorely on a surface marker. We, and others, have demonstrated that the CD133(+) CSCs reside in complex vascular niches, where reciprocal signaling between the CD133(+) CSCs and their microenvironment may govern niche morphogenesis and homeostasis. Herein, we discuss the multifaceted functional role of the CD133(+) cells in the context of their niche, and the potential of targeting CD133 as a niche-dependent approach in effective therapy.
- Activated Neutrophils Induce Epithelial Cell Apoptosis Through Oxidant-Dependent Tyrosine Dephosphorylation of Caspase-8. [JOURNAL ARTICLE]
- Am J Pathol 2014 Feb 28.
Activated neutrophils can injure host cells through direct effects of oxidants on membrane phospholipids, but an ability to induce apoptotic cell death has not previously been reported. We show that neutrophils activated in vivo in patients who have sustained multiple trauma or in vitro by exposure to bacterial lipopolysaccharide promote epithelial cell apoptosis through SHP-1-mediated dephosphorylation of epithelial cell caspase-8. Epithelial cell apoptosis induced by circulating neutrophils from patients who had sustained serious injury depended on the generation of neutrophil-derived reactive oxygen intermediates and was blocked by inhibition of NADPH oxidase or restoration of intracellular glutathione. Caspase-8 was constitutively tyrosine phosphorylated in a panel of resting epithelial cells, but underwent SHP-1-dependent dephosphorylation in response to hydrogen peroxide, activated neutrophils, or inhibition of Src kinases. Cells transfected with a mutant caspase-8 in which tyrosine residues at Tyr397 or Tyr465 are replaced by nonphosphorylatable phenylalanine underwent accelerated apoptosis, whereas either mutation of these residues to phosphomimetic glutamic acid or transfection with the Src kinases Lyn or c-Src inhibited hydrogen peroxide-induced apoptosis. Exposure to either hydrogen peroxide or lipopolysaccharide-stimulated neutrophils increased phosphorylation and activity of the phosphatase SHP-1, increased activity of caspases 8 and 3, and accelerated epithelial cell apoptosis. These observations reveal a novel mechanism for neutrophil-mediated tissue injury through oxidant-dependent, SHP-1-mediated dephosphorylation of caspase-8 resulting in enhanced epithelial cell apoptosis.
- This Month in AJP. [JOURNAL ARTICLE]
- Am J Pathol 2014 Feb 27.
The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
- The BRC Canopy: An Important Player in Bone Remodeling. [JOURNAL ARTICLE]
- Am J Pathol 2014 Feb 20.
This Commentary highlights the article by Andersen et al, which describes structural changes in bone associated with increased bone resorption in osteoporotic post-menopausal women.
- Pigment Epithelium-Derived Factor Improves Metabolic Derangements and Ameliorates Dysregulation of Adipocytokines in Obese Type 2 Diabetic Rats. [JOURNAL ARTICLE]
- Am J Pathol 2014 Feb 13.
Oxidative stress and inflammation in the adipose tissues contribute to the metabolic syndrome. Pigment epithelium-derived factor (PEDF) inhibits vascular inflammation through its anti-oxidative properties. However, it remains unclear whether PEDF could suppress adipocyte inflammation. We investigated the effects of long-term administration or suppression of PEDF on adipocyte inflammation and metabolic derangements in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes with insulin resistance. Circulating and adipose tissue PEDF levels were increased as OLETF rats became more obese and insulin resistant. Long-term administration of PEDF improves metabolic parameters, ameliorates dysregulation of adipocytokines, and suppresses NADPH oxidase-induced oxidative stress and macrophage infiltration in the adipose tissues of OLETF rats, whereas these variables are exacerbated by the knockdown of PEDF by administering siRNAs. Our study suggests that PEDF could improve metabolic derangements by suppressing the inflammatory and oxidative reactions in adipose tissues of OLETF rats. PEDF levels may be elevated as a countersystem against obesity-related metabolic derangements.
- Enhanced F508del-CFTR Channel Activity Ameliorates Bone Pathology in Murine Cystic Fibrosis. [JOURNAL ARTICLE]
- Am J Pathol 2014 Feb 11.
In patients with cystic fibrosis (CF), rib and thoracic vertebral fractures can have adverse effects on lung health because the resulting pain and debilitation can impair airway clearance. The F508del mutation in the CF transmembrane conductance regulator (Cftr) gene induces an osteopenic phenotype in humans and mice. N-butyldeoxynojyrimicin (miglustat), an approved drug for treating type 1 Gaucher disease, was found to normalize CFTR-dependent chloride transport in human F508del CFTR lung cells and in nasal mucosa of F508del CF mice. Herein, we investigated whether targeting F508del-CFTR may rescue the skeletal osteopenic phenotype in murine CF. We found that oral administration of low-dose miglustat (120 mg/kg once a day for 28 days) improved bone mass and microarchitecture in the lumbar spine and femur in F508del mice. The increased bone density was associated with an increased bone formation rate and reduced bone resorption. This effect was associated with increased 17β-estradiol but not with insulin-like growth factor 1 serum levels in miglustat-treated F508del mice. Exposure of primary F508del osteoblasts to miglustat partially restored the deficient CFTR-dependent chloride transport in these bone-forming cells. This study provides evidence that reversal of CFTR-dependent chloride transport in osteoblasts normalizes bone mass and microarchitecture in murine CF. These findings may provide a potential therapeutic strategy to prevent or correct the bone disease in patients with CF.
- Altered Macrophage Phenotype Transition Impairs Skeletal Muscle Regeneration. [JOURNAL ARTICLE]
- Am J Pathol 2014 Feb 11.
Monocyte/macrophage polarization in skeletal muscle regeneration is ill defined. We used CD11b-diphtheria toxin receptor transgenic mice to transiently deplete monocytes/macrophages at multiple stages before and after muscle injury induced by cardiotoxin. Fat accumulation within regenerated muscle was maximal when ablation occurred at the same time as cardiotoxin-induced injury. Early ablation (day 1 after cardiotoxin) resulted in the smallest regenerated myofiber size together with increased residual necrotic myofibers and fat accumulation. However, muscle regeneration after late (day 4) ablation was similar to controls. Levels of inflammatory cells in injured muscle following early ablation and associated with impaired muscle regeneration were determined by flow cytometry. Delayed, but exaggerated, monocyte [CD11b(+)(CD90/B220/CD49b/NK1.1/Ly6G)(-)(F4/80/I-Ab/CD11c)(-)Ly6C(+/-)] accumulation occurred; interestingly, Ly6C(+) and Ly6C(-) monocytes were present concurrently in ablated animals and control mice. In addition to monocytes, proinflammatory, Ly6C(+) macrophage accumulation following early ablation was delayed compared to controls. In both groups, CD11b(+)F4/80(+) cells exhibited minimal expression of the M2 markers CD206 and CD301. Nevertheless, early ablation delayed and decreased the transient accumulation of CD11b(+)F4/80(+)Ly6C(-)CD301(-) macrophages; in control animals, the later tissue accumulation of these cells appeared to correspond to that of anti-inflammatory macrophages, determined by cytokine production and arginase activity. In summary, impairments in muscle regeneration were associated with exaggerated monocyte recruitment and reduced Ly6C(-) macrophages; the switch of macrophage/monocyte subsets is critical to muscle regeneration.
- Identification of Three Molecular and Functional Subtypes in Canine Hemangiosarcoma through Gene Expression Profiling and Progenitor Cell Characterization. [JOURNAL ARTICLE]
- Am J Pathol 2014 Feb 11.
Canine hemangiosarcomas have been ascribed to an endothelial origin based on histologic appearance; however, recent findings suggest that these tumors may arise instead from hematopoietic progenitor cells. To clarify this ontogenetic dilemma, we used genome-wide expression profiling of primary hemangiosarcomas and identified three distinct tumor subtypes associated with angiogenesis (group 1), inflammation (group 2), and adipogenesis (group 3). Based on these findings, we hypothesized that a common progenitor may differentiate into the three tumor subtypes observed in our gene profiling experiment. To investigate this possibility, we cultured hemangiosarcoma cell lines under normal and sphere-forming culture conditions to enrich for tumor cell progenitors. Cells from sphere-forming cultures displayed a robust self-renewal capacity and exhibited genotypic, phenotypic, and functional properties consistent with each of the three molecular subtypes seen in primary tumors, including expression of endothelial progenitor cell (CD133 and CD34) and endothelial cell (CD105, CD146, and αvβ3 integrin) markers, expression of early hematopoietic (CD133, CD117, and CD34) and myeloid (CD115 and CD14) differentiation markers in parallel with increased phagocytic capacity, and acquisition of adipogenic potential. Collectively, these results suggest that canine hemangiosarcomas arise from multipotent progenitors that differentiate into distinct subtypes. Improved understanding of the mechanisms that determine the molecular and phenotypic differentiation of tumor cells in vivo could change paradigms regarding the origin and progression of endothelial sarcomas.