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).
Gupta, K., Li, Q., Fan, J.J., Fong, E.L.S., Song, Z., Mo, S., Tang, H., Ng, I.C., Ng, C.W., Zhuo, S., Dong, C.-Y., Low, B.C., Wee, A., Dan, Y.Y., Kanchanawong, P., So, P., Viasnoff, V., and Yu, H. (2017) Actomyosin Contractility Drives Bile Regurgitation as an Early Response During Obstructive Cholestasis. Journal of Hepatology, 18 March 2017; S0168-8278(17): 30061-30062. DOI: 10.1016/j.jhep.2017.01.026
BACKGROUND & AIMS: A wide range of liver diseases manifest as biliary obstruction, or cholestasis. However, the sequence of molecular events triggered as part of the early hepatocellular homeostatic response in obstructive cholestasis is poorly elucidated. Bile canaliculi are dynamic luminal structures that undergo actomyosin-mediated periodic contractions to propel secreted bile. Additionally, pericanalicular actin is known to accumulate during obstructive cholestasis. Therefore, we hypothesize that the pericanalicular actin cortex undergoes significant remodeling as a regulatory response to obstructive cholestasis.
METHODS: Investigations into the effects of obstructive cholestasis were performed in a bile duct ligated mouse model. To elucidate the role of actomyosin contractility, we used sandwich-cultured hepatocytes transfected with various fluorescently labeled proteins and pharmacological inhibitors of actomyosin contractility.
RESULTS: We report here that actomyosin contractility induces transient deformations along the canalicular membrane, a process we have termed inward blebbing. We show that these membrane intrusions are initiated by local ruptures in the pericanalicular actin cortex; and they typically retract following repair by actin polymerization and actomyosin contraction. However, above a certain osmotic pressure threshold, these inward blebs pinch away from the canalicular membrane into the hepatocyte cytoplasm as large vesicles (2-8 μm). Importantly, we show that these vesicles aid in the regurgitation of bile from the bile canaliculi.
CONCLUSION: Actomyosin contractility induces the formation of bile-regurgitative vesicles, thus serving as an early homeostatic mechanism against increased biliary pressure during cholestasis.
LAY ABSTRACT: Bile canaliculi lumen undergoes cyclic expansion and contraction mediated by bile secretion, and resistance from the surrounding actin bundles. Further expansion due to bile duct blockade leads to the formation of inward blebs and vesicles which carry away excess bile to prevent bile build up in the lumen.
Fong, L.S.E., Toh, T.B., Chow, E., and Yu, H. (2017) 3D culture as a clinically relevant model for personalized medicine. SLAS Technology, March 2017; 1: 2472630317697251. DOI: 10.1177/2472630317697251
Advances in understanding many of the fundamental mechanisms of cancer progression have led to the development of molecular targeted therapies. While molecular targeted therapeutics continue to improve the outcome for cancer patients, tumor heterogeneity among patients, as well as intratumoral heterogeneity, limits the efficacy of these drugs to specific patient subtypes, as well as contributes to relapse. Thus, there is a need for a more personalized approach toward drug development and diagnosis that takes into account the diversity of cancer patients, as well as the complex milieu of tumor cells within a single patient. Three-dimensional (3D) culture systems paired with patient-derived xenografts or patient-derived organoids may provide a more clinically relevant system to address issues presented by personalized or precision medical approaches. In this review, we cover the current methods available for applying 3D culture systems toward personalized cancer research and drug development, as well as key challenges that must be addressed in order to fully realize the potential of 3D patient-derived culture systems for cancer drug development. Greater implementation of 3D patient-derived culture systems in the cancer research field should accelerate the development of truly personalized medical therapies for cancer patients.
Lou, Y.R., Toh, T.C., Tee, Y.H., and Yu, H. (2017) 25-Hydroxyvitamin D3 induces osteogenic differentiation of human mesenchymal stem cells. Scientific Reports, 17 February 2017; 7: 41238. DOI: 10.1038/srep42816
25-Hydroxyvitamin D3 [25(OH)D3] has recently been found to be an active hormone. Its biological actions are demonstrated in various cell types. 25(OH)D3 deficiency results in failure in bone formation and skeletal deformation. Here, we investigated the effect of 25(OH)D3 on osteogenic differentiation of human mesenchymal stem cells (hMSCs). We also studied the effect of 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2D3], a metabolite of 25(OH)D3. One of the vitamin D responsive genes, 25(OH)D3-24-hydroxylase (cytochrome P450 family 24 subfamily A member 1) mRNA expression is up-regulated by 25(OH)D3 at 250-500 nM and by 1α,25-(OH)2D3 at 1-10 nM. 25(OH)D3 and 1α,25-(OH)2D3 at a time-dependent manner alter cell morphology towards osteoblast-associated characteristics. The osteogenic markers, alkaline phosphatase, secreted phosphoprotein 1 (osteopontin), and bone gamma-carboxyglutamate protein (osteocalcin) are increased by 25(OH)D3 and 1α,25-(OH)2D3 in a dose-dependent manner. Finally, mineralisation is significantly increased by 25(OH)D3 but not by 1α,25-(OH)2D3. Moreover, we found that hMSCs express very low level of 25(OH)D3-1α-hydroxylase (cytochrome P450 family 27 subfamily B member 1), and there is no detectable 1α,25-(OH)2D3 product. Taken together, our findings provide evidence that 25(OH)D3 at 250-500 nM can induce osteogenic differentiation and that 25(OH)D3 has great potential for cell-based bone tissue engineering.