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  • Host pathogen interaction is a

    2018-11-12

    Host-pathogen interaction is a balancing act as viruses evolved to have strategies to evade the host defense system. HCV NS3, core and NS5A proteins are involved in immune evasion by modulating specific and innate immune pathways (Basu et al., 2001; Horner and Gale, 2013). NS3 protease can effectively inactivate RIG-I by proteolysis, thus folate analogue negating the RIG-I mediated sensing of HCV RNA and activation of downstream IRF-3 and NF-kB effectors (Korth and Katze, 2000; Gale and Foy, 2005). Besides IFN-α, IL28 or IFN-λ, a type III IFN has been shown to inhibit HCV replication by inducing ISGs (Thomas et al., 2012; Zhou et al., 2014). Robust viral production is observed in sub-clones of Huh-7 cell line that lack the innate immune sensor RIG-I and Huh-7 based cell lines have been commonly used for HCV studies (Lindenbach et al., 2005; Sumpter et al., 2005; Wakita et al., 2005; Pietschmann et al., 2006; Chu et al., 2013). Pluripotent stem cell-derived hepatic folate analogue is a useful model system for studying the interaction of innate immune factors with hepatic pathogens, including HCV, hepatitis B virus (HBV) and dengue virus. A previous study reported that the iPSC Hepatocytes-like cells (iHLC) in response to HCV infection up-regulated antiviral inflammatory genes (Schwartz et al., 2012). To further improve the utility of human pluripotent stem cell lines for modeling patho-physiological processes of innate immune system, individual or combination of ISG knock-out cell lines could be established. Recent advances in gene editing technologies through designer nucleases, Zinc-finger nucleases (ZFN) and Transcription activator-like effector nucleases (TALENs) as well as CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system, facilitate precise editing of human genome by double-strand DNA breaks (Ding, Lee, et al., 2013a,b; Ran et al., 2013). Utilizing human pluripotent stem cell lines for modeling processes of innate immune system can expand beyond studying viral infection; furthermore, it can support human clinical trials by evaluating the cell candidate population for transplant by measuring the presence of an intact immune response to improve clinical outcome. For instance, retinal pigment epithelium cells derived from iPSCs are currently being evaluated in human clinical trials for an eye disorder and several other stem cell-based preclinical studies are poised for human testing (Trounson et al., 2011; Riken, 2013). Due to immuno-suppressive treatment following allogeneic cell transplant and natural exposure to pathogens in the environment, the recipients have the risk of complications from infectious diseases. To increase the chance of better therapeutic outcome, the cell candidate for transplant can be evaluated for presence of functional innate immune system.
    Conclusion The following are the Supplementary data related to this article.
    Acknowledgments Huh-7.5.1 cell line was a gift from Francis V. Chisari (The Scripps Research Institute, USA). This work was funded by the Cedars-Sinai Medical Center\'s Institutional Research Award and National Center for Advancing Translational Sciences, Grant UL1TR000124 to V.A. and NIHR01DK090794 grant to S.W.F.
    Introduction Activin/Nodal/TGF-β, BMP, and Wnt signaling play pivotal roles in regulating mesoderm and cardiac specification during embryo development (Arnold and Robertson, 2009; Buckingham et al., 2005; Tam and Loebel, 2007; David et al., 2008; Naito et al., 2006; Ueno et al., 2007; Burridge et al., 2012). Significant progress has been made in the cardiac differentiation process by modulating Activin, BMP, and Wnt pathways, which can efficiently drive differentiation to over 80% purity of CM (Burridge et al., 2014; Kattman et al., 2011; Lian et al., 2012; Yang et al., 2008; Zhang et al., 2012; Zhu et al., 2011). Using an adherent cell culture platform, one study revealed that using 2 small Wnt pathway modulators to sequentially activate and then inhibit Wnt signaling at different differentiation stages of the culture is sufficient to drive cardiac differentiation and generate CM with high purity (Lian et al., 2012). In spite of this, adherent culture systems have limited scalability and are not practical to support the anticipated CM requirements of clinical trials. Alternatively, using an embryoid body (EB) differentiation method, a complex cardiac induction procedure involving stage-specific treatments with growth factors and small molecules to modulate Activin/Nodal, BMP, and Wnt pathways has been reported to be effective in cardiac differentiation in a suspension culture system (Kattman et al., 2011; Yang et al., 2008). However, the process of generating EBs is inefficient, rendering this method impractical for large scale CM production. An additional limitation of these approaches for scale-up application is that both methods are based on the expansion of the hPSCs in adherent culture and the subsequent CM differentiation process in either adherent culture or as EBs. The labor intensiveness and limited scalability of current processes have been the primary bottle necks to the large scale production of CM for clinical applications of hPSC-derived CM.