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| |  Vaccines are urgently needed to slow the spread of HIV and hepatitis C virus (HCV), which together infect an estimated 240 million people, most of them in developing countries. To prepare a human vaccine, investigators need an animal model that can help them screen and prioritize vaccine candidates. Genetic engineering techniques have the potential to help researchers create laboratory mice with immune systems and livers similar to those of humans, allowing for evaluation of vaccine candidates prior to clinical trials in humans.
Dr. Deng and his colleagues are working to improve techniques for creating mouse models with immune systems and livers that are similar enough to humans to allow testing of potential HIV and HCV vaccines. The team is working to create chimerical mouse models with hematopoietic cells (HSCs) and hepatocytes differentiated from human embryonic stem (hES) cells.
Team members are now working to further characterize, in vitro and in vivo, the liver progenitor cells generated during hES differentiation. They expect hepatic stem/progenitor cells derived from hES cells could be used as an alternative strategy to humanize the injured mouse liver. |
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| | | Obtaining engraftable hematopoietic stem cells and hepatocytes by inducing the differentiation of human embryonic stem cells | | | | | Establishing small animal models with humanized immune systems for HIV-1 vaccine testing by transplanting cell derivations | | | | | Establishing small animal models with a humanized liver for HCV vaccine testing by transplanting cell derivations | | | | | Evaluating the reconstituted immune system and repopulated liver in transplanted mice | | |
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| | | Developed a strategy to direct hES cell differentiation into hepatic cells. After induction, about 70 percent of the differentiated cells express hepatic markers. The differentiated cells possess liver functions including LDL uptake and glycogen storage, and can be infected by HIV-HCV pseudotype virus, suggesting that the cells could be used to study HCV infection. Investigators transplanted the hepatic cells derived from hES cells into injured SCID mice. Preliminary data show that the transplanted cells can engraft and form clusters in the mouse liver. | | | | | Identified the liver progenitor cells generated during hES differentiation. These cells expressed the early hepatic marker, and can differentiate into hepatocytes or cholangiocytes. They can proliferate in vitro, as detected by Ki67 expression. | | | | | Found that short-term BMP-4 treatment of hES cells can induce mesoderm progenitors with high efficiency, as measured by brachyury expression and several other markers. By using BMP-4 as an induction factor, investigators developed for the first time a serum-free and feeder-free system to induce mesoderm generation from hES cells in adherent cultures without embryoid body formation. The generated mesodermal cells can further differentiate into hematopoietic cells and cardiomyocytes. | | | | | Investigators also found that a newly isolated gene, Lycat, plays an important role in the early specification of hematopoietic and endothelial cells, probably acting at the level of the hemangioblast. Based on these results, they developed a new strategy to direct hES cell differentiation into hematopoietic stem cells, inducing hES cell differentiation into hematopoietic lineage through mimicking the in vivo embryogenesis process. With this new strategy, investigators were able to obtain large numbers of CD34+ cells from hES cell differentiation. They are now evaluating the engraftment efficiency of the differentiated cells in NOD/SCID mice. | | |
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| | | Dr Rudi Balling, German Centre for Biotechnology (GBF), Braunschweig, Germany - DE | | | | | Dr. Jingwei Xiong, Harvard University, Massachusetts, United States - US | | |
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