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  • br Results br Discussion We

    2018-10-22


    Results
    Discussion We have demonstrated that the hPSC-derived HBCs could be maintained on a human LN111-coated dish in an integrin α6- and β1-dependent manner (Figure 1). It is known that undifferentiated hPSCs could be maintained on a human LN511-coated dish but not on a human LN111-coated dish (Rodin et al., 2010). This might suggest that human LN111 has the potential not only to selectively maintain HBCs, but also to eliminate residual undifferentiated cells. Our hepatoblast-like purchase ldv could efficiently proliferate for more than 3 months on a human LN111-coated dish (Figure 2). In the human liver development (during 5–10 weeks gestation), laminin is observed in both the perisinusoidal space and portal tracts (Couvelard et al., 1998). The expression of laminin is localized around the periportal biliary trees during the later stage of liver development (Couvelard et al., 1998). Hepatic stem cells reside around the hepatic portal area (Clément et al., 1988). It is also known that laminin is accumulated around oval cells although laminin is not expressed around quiescent mature hepatocytes (Paku et al., 2001). These facts suggest that laminin plays an important role in the maintenance and proliferation of hepatoblasts. The hPSC-derived HBC P10 and clone were positive for hepatoblast markers (AFP, ALB, CYP3A7, and I-CAM), but negative for hepatic stem cell markers (N-CAM and Claudin 3) (Figure 3) (Schmelzer et al., 2007). Although the hPSC-derived HBCs were able to expand on human LN111-coated dish, Schmelzer et al. showed that human hepatoblasts do not proliferate under a monolayer culture condition, but human hepatic stem cells could self-replicate for more than 6 months (Schmelzer et al., 2007). Although further investigations of the hepatoblast characteristics in the hPSC-derived HBCs will be needed in the future, the results in the present study suggest that the characteristics of hPSC-derived HBCs expanded on human LN111-coated dishes were similar to those in human hepatoblasts isolated from the human liver (Schmelzer et al., 2007; Zhang et al., 2008). The hPSC-derived HBCs had the ability to integrate into the mouse liver parenchyma (Figure 5), in the manner of human hepatic stem cells or hepatoblasts (Schmelzer et al., 2007). The human ALB serum levels (approximately 20–70 ng/ml) in mice transplanted with the hESC-derived HBC P0 or HBC P10 were comparable to those in the previous paper in which the hESC-derived definitive endoderm cells, hepatoblasts, and hepatocyte-like cells were transplanted into mice (Liu et al., 2011), but were lower than those of human liver chimeric mice (Tateno et al., 2004). Human ALB serum levels would increase if more suitable host mice, such as urokinase plasminogen activator-SCID mice were used (Tateno et al., 2004).
    Experimental Procedures
    Acknowledgments
    Introduction BRCA1/2 mutations are autosomal-dominant mutations that dramatically increase the risk for developing breast and ovarian cancer, and to a lesser extent other malignancies, such as melanoma, pancreatic cancer, and prostate cancer (Futreal et al., 1994; Lancaster et al., 1996; Miki et al., 1994). The BRCA1 and BRCA2 tumor-suppressor proteins play roles in transcriptional regulation and DNA repair (Turner et al., 2004). BRCA1 also participates in cell-cycle regulation (McPherson et al., 2004), polyadenylation of messenger RNA (mRNA) (Kleiman et al., 2005), and ubiquitinylation (Baer and Ludwig, 2002). The cancers that arise in patients with inherited BRCA1 mutations appear to be more aggressive than those in patients with BRCA2 mutations or sporadic breast tumors. This aggressiveness is thought to result at least in part from the fact that BRCA1-deficient tumors, but not BRCA2-deficient tumors, are usually estrogen receptor (ER) and progesterone receptor (PR) negative (Turner et al., 2004) and therefore unresponsive to hormonal therapies. These observations suggest that the shared DNA repair functions of BRCA1 and BRCA2 do not solely account for differences in cancer incidence among patients with mutations in these genes. Evidence also indicates that cancer risk differs depending on the location of the mutation in the BRCA sequences (Risch et al., 2006). Examination of different BRCA1/2 mutant cells that are prone to tumor formation will identify new BRCA1 and BRCA2 tumor-suppressor functions.