IGF-1R Promotes Symmetric Self-Renewal and Migration of Alkaline Phosphatase+ Germ Stem Cells through HIF-2α-OCT4/CXCR4 Loop under Hypoxia.

Hypoxia cooperates with endocrine signaling to maintain the symmetric self-renewal proliferation and migration of embryonic germline stem cells (GSCs). However, the lack of an appropriate in vitro cell model has dramatically hindered the understanding of the mechanism underlying this cooperation. Here, using a serum-free system, we demonstrated that hypoxia significantly induced the GSC mesenchymal transition, increased the expression levels of the pluripotent transcription factor OCT4 and migration-associated proteins (SDF-1, CXCR4, IGF-1, and IGF-1R), and activated the cellular expression and translocalization of the CXCR4-downstream proteins ARP3/pFAK. The underlying mechanism involved significant IGF-1/IGF-1R activation of OCT4/CXCR4 expression through HIF-2α regulation. Picropodophyllin-induced inhibition of IGF-1R phosphorylation significantly suppressed hypoxia-induced SDF-1/CXCR4 expression and cell migration. Furthermore, transactivation between IGF-1R and CXCR4 was involved. In summary, we demonstrated that niche hypoxia synergistically cooperates with its associated IGF-1R signaling to regulate the symmetric division (self-renewal proliferation) and cell migration of alkaline phosphatase-positive GSCs through HIF-2α-OCT4/CXCR4 during embryogenesis.

Comparison of collagen proportionate areas in liver fibrosis quantification between chronic hepatitis B and C.

Few studies have compared the distinct hepatic collagen morphometrics of chronic hepatitis B (CHB) and chronic hepatitis C (CHC). This study compared the discrepancies between CHB and CHC in liver fibrosis (F) quantification by using the collagen proportionate area (CPA) and liver stiffness (LS) measured with shear wave velocity (SWV).This study enrolled 274 eligible consecutive patients diagnosed with CHB (n = 137) or CHC (n = 137). Their ages ranged from 20 to 80 years (median = 50). In total, 154 patients (56.2%) were male. Participant LS was measured by using acoustic radiation force impulse elastography preceding an immediate percutaneous liver biopsy. The total proportion of the collagen stained with picrosirius red to the total tissue area was expressed as the CPA percentage, which was stratified into portal-bridging (PB) and perisinusoidal (PS) proportionate areas (PAs).Based on the METAVIR F staging system, 36 (26.3%), 36 (26.3%), 28 (20.4%), and 37 (27.0%) participants in the CHB group and 34 (24.8%), 45 (32.9%), 34 (24.8%), and 24 (17.5%) participants in the CHC group were staged as F1, F2, F3, and F4, respectively. Both the total CPAs and PBPAs were significantly (P < 0.05) higher in the CHC group than in the CHB group within all F-stratified subgroups. The SWVs were significantly (P < 0.05) higher in the CHC group than in the CHB group only within the F2, F3, and F4 subgroups. However, the PSPAs did not differ significantly between the CHC and CHB groups within all subgroups. Multiple regression analysis revealed that viral hepatitis etiology (P < 0.001), METAVIR F stages (P < 0.001), and platelet count (P = 0.007) were independent factors correlated with the CPA (R = 0.543, P < 0.001).In conclusion, both the F stage-stratified CPAs and SWVs tended to be higher in cases of CHC than in those of CHB. The type of viral hepatitis significantly affected both the CPA and SWV values. The PBPAs were more closely correlated with F stages and SWV than were the PSPAs.

Head-to-Head Comparison between Collagen Proportionate Area and Acoustic Radiation Force Impulse Elastography in Liver Fibrosis Quantification in Chronic Hepatitis C.

BACKGROUND: The aim of this study was to compare the diagnostic performances of the collagen proportionate area (CPA) and liver stiffness measurement (LSM) for liver fibrosis quantification in chronic hepatitis C (CHC). METHODS: A total of 137 eligible consecutive Taiwanese patients (74 women and 63 men; age 21-80 years; median age 54 years), with CHC underwent LSM by using acoustic radiation force impulse (ARFI) elastography and an immediate percutaneous liver biopsy for METAVIR scoring. Liver tissue sections were stained using picrosirius red. Areas of the stained collagen and the tissue parenchyma were calculated in pixels. The ratio between the two areas was expressed as a CPA percentage. The result of LSM was presented as shear wave velocity (SWV). RESULTS: METAVIR fibrosis (F) stages were dichotomized using the CPA (%) and SWV (m/s), and the optimal cut-off values were 7.47 and 1.59 for F1 versus F2-4; 12.56 and 1.73 for F1, 2 versus F3, 4; 15.32 and 1.96 for F1-3 versus F4. To dichotomize F1 versus F2-4, the areas under receiver operating characteristic curves for the CPA was 0.9349 (95% confidence interval: 0.8943-0.9755) and for SWV was 0.8434 (0.7762-0.9105) (CPA versus SWV, P = 0.0063). For F1, 2 versus F3, 4, the CPA was 0.9436 (0.9091-0.9781); SWV was 0.8997 (0.8444-0.9551) (P = 0.1587). For F1-3 versus F4, the CPA was 0.8647 (0.7944-0.9349); SWV was 0.9036 (0.8499-0.9573) (P = 0.2585). The CPA could be predicted in a linear regression formula by using SWV and platelet count (R2 = 0.524). CONCLUSIONS: The CPA and ARFI elastography are promising tools for liver fibrosis evaluation. The CPA was superior to ARFI elastography in the diagnosis of significant fibrosis (≥ F2). The CPA may be independent of severe necroinflammation, which may augment liver stiffness.

Exposure to environmental tobacco smoke, human E-cadherin C-160A polymorphism, and childhood asthma.

BACKGROUND: Environmental tobacco smoke (ETS) is a risk factor for asthma. Importantly, cigarette smoke can decrease the adherence of epithelial cells and increase detachment. The adhesion molecule E-cadherin (CDH1) has an essential role in the formation of epithelial junction. Turnover of the extracellular matrix, which is characterized by airway remodeling, depends on the imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs). OBJECTIVE: To evaluate the effects of ETS exposure and CDH1, MMP-3, and TIMP-1 genetic polymorphisms on childhood asthma. METHODS: The CDH1 C-160A, MMP-3 -1171, and TIMP-1 T372C genotypes were identified by polymerase chain reaction in 299 asthmatic children and 383 healthy controls. RESULTS: More ETS exposure (>5 vs 0 cigarettes/day; odds ratio [OR], 1.45; 95% confidence interval [CI], 1.05-2.01) and the presence of CDH1 AA/CA genotypes (OR, 1.53; 95% CI, 1.08-2.17) were associated with childhood asthma. Compared with children with less ETS exposure (0-5 cigarettes/day) and the CDH1 CC genotype, those with less ETS exposure and the CDH1 AA/CA genotypes and those with more ETS exposure and the CDH1 CC genotype had a moderate risk of asthma. The greatest risk for asthma was in children with more ETS exposure and the CDH1 AA/CA genotypes (OR, 3.03; 95% CI, 1.81-5.06), and this interaction between CDH1 polymorphism and ETS exposure was significant. In addition, asthma cases with more ETS exposure or the CDH1 AA/CA genotypes had obviously increased eosinophil counts. CONCLUSION: Susceptible CDH1 genotypes might modulate the development of asthma, especially for children exposed to ETS.