Co-culture Model for Hepatitis B Virus Infection Using iPSC-Derived Liver Progenitor Cells and Liver Sinusoidal Endothelial Cells.

In order to understand the complicated life cycle of hepatitis B virus (HBV), it is necessary to develop a co-culture system for HBV infection using various liver cells. We have already developed culture systems to generate liver progenitor cells (LPCs), hepatocytes, and liver sinusoidal endothelial cells (LSECs) from human induced pluripotent cells (iPSCs). Using those cells, we established a co-culture system to study HBV infection and replication in vitro.

Modulation of hepatitis B virus infection by epidermal growth factor secreted from liver sinusoidal endothelial cells.

Hepatocytes derived from human iPSCs are useful to study hepatitis B virus (HBV) infection, however infection efficiency is rather poor. In order to improve the efficiency of HBV infection to iPSC-derived hepatocytes, we set a co-culture of hepatocytes with liver non-parenchymal cells and found that liver sinusoidal endothelial cells (LSECs) enhanced HBV infection by secreting epidermal growth factor (EGF). While EGF receptor (EGFR) is known as a co-receptor for HBV, we found that EGF enhanced HBV infection at a low dose of EGF, whereas EGF at a high dose suppressed HBV infection. EGFR is internalized by clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE) pathways depending on the dose of EGF. At a high dose of EGF, the endocytosed EGFR via CIE is degraded in the lysosome. This study is the first to provide evidence that HBV is endocytosed via CME and CIE pathways at a low and high dose of EGF, respectively. In conclusion, we developed an in vitro system of HBV infection using iPSC-derived liver cells, and show that EGF secreted from LSECs modulates HBV infection in a dose dependent manner.

An In Vitro Human Liver Model by iPSC-Derived Parenchymal and Non-parenchymal Cells.

During liver development, hepatoblasts and liver non-parenchymal cells (NPCs) such as liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs) constitute the liver bud where they proliferate and differentiate. Accordingly, we reasoned that liver NPCs would support the maturation of hepatocytes derived from human induced pluripotent stem cells (hiPSCs), which usually exhibit limited functions. We found that the transforming growth factor ß and Rho signaling pathways, respectively, regulated the proliferation and maturation of LSEC and HSC progenitors isolated from mouse fetal livers. Based on these results, we have established culture systems to generate LSECs and HSCs from hiPSCs. These hiPSC-derived NPCs exhibited distinctive phenotypes and promoted self-renewal of hiPSC-derived liver progenitor cells (LPCs) over the long term in the two-dimensional culture system without exogenous cytokines and hepatic maturation of hiPSC-derived LPCs. Thus, a functional human liver model can be constructed in vitro from the LPCs, LSECs, and HSCs derived from hiPSCs.

Optimization of a Multi-Product Intra-Supply Chain System with Failure in Rework.

Globalization has created tremendous opportunities, but also made business environment highly competitive and turbulent. To gain competitive advantage, management of present-day transnational firms always seeks options to trim down various transaction and coordination costs, especially in the area of controllable intra-supply chain system. This study investigates a multi-product intra-supply chain system with failure in rework. To achieve maximum machine utilization, multiple products are fabricated in succession on a single machine. During the process, production of some defective items is inevitable. Reworking of nonconforming items is used to reduce the quality cost in production and achieving the goal of lower overall production cost. Because reworks are sometimes unsuccessful, failures in rework are also considered in this study. Finished goods for each product are transported to the sales offices when the entire production lot is quality assured after rework. A multi-delivery policy is used, wherein fixed quantity n installments of the finished lot are transported at fixed intervals during delivery time. The objective is to jointly determine the common production cycle time and the number of deliveries needed to minimize the long-term expected production-inventory-delivery costs for the problem. With the help of a mathematical model along with optimization technique, the optimal production-shipment policy is obtained. We have used a numerical example to demonstrate applicability of the result of our research.

Producer-retailer integrated EMQ system with machine breakdown, rework failures, and a discontinuous inventory issuing policy.

This study develops two extended economic manufacturing quantity (EMQ)-based models with a discontinuous product issuing policy, random machine breakdown, and rework failures. Various real conditions in production processes, end-product delivery, and intra-supply chains such as a producer-retailer integrated scheme are examined. The first model incorporates a discontinuous multi-delivery policy into a prior work (Chiu et al. in Proc Inst Mech Eng B J Eng 223:183-194, 2009) in lieu of their continuous policy. Such an enhanced model can address situations in supply chain environments, where finished products are transported to outside retail stores (or customers). The second model further combines retailer's stock holding costs into the first model. This extended EMQ model is applicable in situations in present-day manufacturing firms where finished products are distributed to company's own retail stores (or regional sales offices) and stocked there for sale. Two aforementioned extended EMQ models are investigated, respectively. Mathematical modeling along with iterative algorithms are employed to derive the optimal production run times that minimize the expected total system costs, including the costs incurred in production units, transportation, and retail stores, for these integrated EMQ systems. Numerical examples are provided to demonstrate the practical application of the research results.