We share the VISION of EDUCATING ambitious young scientists and engineers to make impacts beyond individual efforts through team projects and collaborative learning in academia and industry.
Understand and control liver regeneration and chronic disease progression. We TRANSLATE technologies and knowledges into solutions for drug development, diagnostics and therapeutics.
Quantitative analysis of the dynamic process of liver regeneration and chronic liver diseases.
Investigating the formation and dynamic maintenance of inter-cellular tissue space such as bile canaliculi and sinusoids that define liver functions.
Developing novel and useful biomaterials, cell sources, and analytics for long-term maintenance of highly functional liver cells in culture.
Developing robust, scalable, low cost and predictive in vitro drug and pathogen testing platforms.
Respect : every LCTE member is important and yet consciously sensitive to other members and the collective impacts. Decisions incorporate inputs from all the stakeholders for fairness and transparency.
Professionalism: every LCTE member strives to attain ever higher quality and standard of her/his own work through mutual empowerment, critique and support to each other.
No-walls culture: solutions to real-life problems can never be confined within artificially-created boundaries (organizational, disciplinary, cultural, inter-personal, or mental inertia).
Li, H., Venkatraman, L., Narmada, B.C., White, J.K., Tucker-Kellogg, L., and Yu, H. (2017) Computational modeling of bistable TGF-β1 activation: the switch between two steady states is accompanied by a switch between positive and negative feedback.BMC Systems Biology, 21 December 2017; 11(Suppl 7): 136. DOI: 10.1186/s12918-017-0508-z
Bistable behaviors are prevalent in cell signaling and can be modeled by ordinary differential equations (ODEs) with kinetic parameters. A bistable switch has recently been found to regulate the activation of transforming growth factor-β1 (TGF-β1) in the context of liver fibrosis, and an ordinary differential equation (ODE) model was published showing that the net activation of TGF-β1 depends on the balance between two antagonistic sub-pathways. Through modeling the effects of perturbations that affect both sub-pathways, we revealed that bistability is coupled with the signs of feedback loops in the model. We extended the model to include calcium and Krüppel-like factor 2 (KLF2), both regulators of Thrombospondin-1 (TSP1) and Plasmin (PLS). Increased levels of extracellular calcium, which alters the TSP1-PLS balance, would cause high levels of TGF-β1, resembling a fibrotic state. KLF2, which suppresses production of TSP1 and plasminogen activator inhibitor-1 (PAI1), would eradicate bistability and preclude the fibrotic steady-state. Finally, the loop PLS − TGF-β1 − PAI1 had previously been reported as negative feedback, but the model suggested a stronger indirect effect of PLS down-regulating PAI1 to produce positive (double-negative) feedback in a fibrotic state. Further simulations showed that activation of KLF2 was able to restore negative feedback in the PLS − TGF-β1 − PAI1 loop. Using the TGF-β1 activation model as a case study, we showed that external factors such as calcium or KLF2 can induce or eradicate bistability, accompanied by a switch in the sign of a feedback loop (PLS − TGF-β1 − PAI1) in the model. The coupling between bistability and positive/negative feedback suggests an alternative way of characterizing a dynamical system and its biological implications.
Fong, L.S.E., Huynh, T.H., Benoukraf, T., Toh, T.B., Lin. X., Liu, Z.J., Hooi, L., Mohd Abdul Rashid, M., Chow. E.K.H., and Yu, H. (2018) Generation of Matched Patient-Derived Xenograft In Vitro-In Vivo Models Using 3D Macroporous Hydrogels for the Study of Liver Cancer. Biomaterials, March 2018; 159: 229-240. DOI: 10.1016/j.biomaterials.2017.12.026
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, often manifesting at the advanced stage when cure is no longer possible. The discrepancy between preclinical findings and clinical outcome in HCC is well-recognized. So far, sorafenib is the only targeted therapy approved as first-line therapy for patients with advanced HCC. There is an urgent need for improved preclinical models for the development of HCC-targeted therapies. Patient-derived xenograft (PDX) tumor models have been shown to closely recapitulate human tumor biology and predict patient drug response. However, the use of PDX models is currently limited by high costs and low throughput. In this study, we engineered in vitro conditions conducive for the culture of HCC-PDX organoids derived from a panel of 14 different HCC-PDX lines through the use of a three-dimensional macroporous cellulosic sponge system. To validate the in vitro HCC-PDX models, both in vivo and in vitro HCC-PDX models were subjected to whole exome sequencing and RNA-sequencing. Correlative studies indicate strong concordance in genomic and transcriptomic profiles as well as intra-tumoral heterogeneity between each matched in vitro-in vivo HCC-PDX pairs. Furthermore, we demonstrate the feasibility of using these in vitro HCC-PDX models for drug testing, paving the way for more efficient preclinical studies in HCC drug development.
Luo, X., Gupta, K., Ananthanarayanan, A., Wang, Z., Xia, L., Li, A., Sakban, R., Liu, S., and Yu, H. (2018) Directed Differentiation of Adult Liver Derived Mesenchymal Like Stem Cells into Functional Hepatocytes. Scientific Reports, 8: 2818. DOI: 0.1038/s41598-018-20304-5
Shortage of functional hepatocytes hampers drug safety testing and therapeutic applications because mature hepatocytes cannot be expanded and maintain functions in vitro. Recent studies have reported that liver progenitor cells can originate from mature hepatocytes in vivo. Derivation of proliferating progenitor cells from mature hepatocytes, and re-differentiation into functional hepatocytes in vitro has not been successful. Here we report the derivation of novel mesenchymal-like stem cells (arHMSCs) from adult rat hepatocytes. Immunofluorescence and flow cytometry characterization of arHMSCs found expression of mesenchymal markers CD29, CD44, CD90, vimentin and alpha smooth muscle actin. These arHMSCs proliferated in vitro for 4 passages yielding 104 fold increase in cell number in 28 days, and differentiated into hepatocyte-like cells (arHMSC-H). The arHMSC-H expressed significantly higher level of hepatocyte-specific markers (200 fold for albumin and 6 fold for Cyp450 enzymes) than arHMSCs. The arHMSC-H also demonstrated dose response curves similar to primary hepatocytes for 3 of the 6 paradigm hepatotoxicants tested, demonstrating utility in drug safety testing applications.