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 microenvironment impact on chronic liver 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 contraction and propagation mechanism of secretory lumen such as bile canaliculi.
Developing novel and useful biomaterials, cell sources, and analytics for long-term maintenance of highly functional epithelial cells in culture.
Developing robust, scalable, low cost and predictive in vitro drug and toxin testing platforms.
Respect : every TMBL 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 TMBL 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).
Sheetz, M., and Yu, H. (2018) The Cell as a Machine, Cambridge University Press, ISBN: 9781107052734.
This unique introductory text has been written by a Lasker Award winning cell biologist; and his PhD student who turned into a biomedical engineer who innovates multiple technologies into award winning companies. It is based on the content and to serve as the text for a course, "Cell as a Machine”, offered by leading universities in the USA and Asia. The course started in 2003 as W3150/4150 in Columbia University, and then taught as course 2.799 in Massachusetts Institute of Technology, and MB5101 in National University of Singapore since 2009, which was extended in different years to Penn, Georgia Tech, UIUC, UC Berkeley/San Diego/Irvine/Davis/Merced, City College of New York, Minnesota, Wash U St Louis, Wisconsin, Boston U and Texas A&M in the US, Hong Kong UST and Zhejiang University in Asia.
The text explains cell functions using the engineering principles of robust devices. Adopting a process-based approach to understanding cell and tissue biology, it describes the molecular and mechanical features that enable the cell to be robust in operating its various components, and explores the ways in which molecular modules respond to environmental signals to execute complex functions. The design and operation of a variety of complex functions are covered, including engineering lipid bilayers to provide fluid boundaries and mechanical controls, adjusting cell shape and forces with dynamic filament networks, and DNA packaging for information retrieval and propagation. Numerous problems, case studies and application examples help readers connect theory with practice, and solutions for instructors and videos of lectures accompany the book online. Assuming only basic mathematical knowledge, this is an invaluable resource for graduate and senior undergraduate students taking single-semester courses in cell mechanics, biophysics, mechanobiology, and cell/tissue biology from a fresh perspective.
Uniquely links together the biology, biophysics, and engineering principles underlying cell functions
Avoids complex mathematical treatments, making it accessible to students with only a basic mathematical background
Additional information about many of the functions described in the book can be found online at www.mechanobio.info
Yu, Y., Wang, J., Ng, C.W., Ma, Y., Mo, S., Fong, L.S.E., Xing, J., Song, Z., Xie, Y., Si, K., Wee, A., Welsch, R.E., So, P.T.C., and Yu, H. (2018) Deep learning enhances automated scoring of liver fibrosis stages. Scientific Reports, 30 October 2018; 8: 16016. DOI: 10.1038/s41598-018-34300-2
Current liver fibrosis scoring by computer-assisted image analytics is not fully automated as it requires manual preprocessing (segmentation and feature extraction) typically based on domain knowledge in liver pathology. Deep learning-based algorithms can potentially classify these images without the need for preprocessing through learning from a large dataset of images. We investigated the performance of classification models built using a deep learning-based algorithm pre-trained using multiple sources of images to score liver fibrosis and compared them against conventional non-deep learning-based algorithms - artificial neural networks (ANN), multinomial logistic regression (MLR), support vector machines (SVM) and random forests (RF). Automated feature classification and fibrosis scoring were achieved by using a transfer learning-based deep learning network, AlexNet-Convolutional Neural Networks (CNN), with balanced area under receiver operating characteristic (AUROC) values of up to 0.85–0.95 versus ANN (AUROC of up to 0.87–1.00), MLR (AUROC of up to 0.73–1.00), SVM (AUROC of up to 0.69–0.99) and RF (AUROC of up to 0.94–0.99). Results indicate that a deep learning-based algorithm with transfer learning enables the construction of a fully automated and accurate prediction model for scoring liver fibrosis stages that is comparable to other conventional non-deep learning-based algorithms that are not fully automated.
Gupta, K., Ng, I.C., Low, B.C., and Yu, H. (2019) Bile Canaliculi Contractility Is Regulated by Canalicular Pressure Sensing via PIEZO1.Biophysical Journal, , 15 February 2019; 116(3 supplement 1): 376a-377a. DOI:10.1016/j.bpj.2018.11.2048
Hepatocytes have the ability to form tubular compartment known as bile canaliculi (BC). These BC are secretory lumens which expand and contract to propel bile, failure to which can lead to cholestasis and jaundice. However, the mechanism of BC expansion and contraction is unknown. Previously, we have reported that the dynamic nature of BC is an interplay of the canalicular pressure and the pericanalicular actomyosin. Here we examined the role of BC calcium in regulating the BC contractions using various calcium probes and live imaging of BC contractions. We find that the BC contractions are associated with the release of Ca 2+ from BC and transient increase of Ca 2+ in the cytoplasm near canaliculi. Furthermore, we also found that the release of Ca 2+ from BC is dependent on the membrane tension sensing via mechanosensitive cation channel: PIEZO-1, as the presence of 10μM GsMTx-4 (PIEZO-1 inhibitor) inhibit calcium release from the BC and BC contractility is enhanced in presence of YODA1 (PIEZO-1 activator). BC expand due to secretion via transporter proteins. However, when a threshold volume is reached, increased membrane tension is sensed by PIEZO-1 and it open up to release Ca 2+ into cell. This Ca 2+ causes actomyosin to contract BC and this cycle repeats itself to periodically expand and contract BC. This novel mechanism present in BC to regulate of its own contractility by releasing Ca 2+ in the cell above a certain membrane tension provides a mechanism to make this system autonomous. This study also opens up new avenues to study similar autonomous contractility in other lumenal structures present in salivary glands, mammary glands and pancreas.
Tasnim, F., Xing, J., Huang, X., Mo, S., Wei, X., Tan, M.-H. and Yu, H. (2019) Generation of Mature Kupffer Cells from Human Induced Pluripotent Stem Cells. Biomaterials, February 2019; 192: 337-391. DOI: 10.1016/j.biomaterials.2018.11.016
Liver macrophages, Kupffer cells (KCs), play a critical role in drug-induced liver injury (DILI) and liver diseases including cholestasis, liver fibrosis and viral hepatitis. Application of KCs in in vitro models of DILI and liver diseases is hindered due to limited source of human KCs. In vivo, KCs originate from MYB-independent macrophage progenitors, which differentiate into liver-specific macrophages in response to hepatic cues in the liver. Here, we recapitulated KCs ontogeny by differentiation of MYB-independent iPSCs to macrophage-precursors and exposing them to hepatic cues to generate iPSC-derived KCs (iKCs). iKCs expressed macrophage markers (CD11/CD14/CD68/CD163/CD32) at 0.3-5 folds of primary adult human KCs (pKCs) and KC-specific CLEC-4F, ID1 and ID3. iKCs phagocytosed and secreted IL-6 and TNFα upon stimulation at levels similar to pKCs but different from non-liver macrophages. Hepatocyte-iKCs co-culture model was more sensitive in detecting hepatotoxicity induced by inflammation-associated drugs, Acetaminophen and Trovafloxacin, and Chlorpromazine-induced cholestasis when compared to hepatocytes alone. Overall, iKCs were mature, liver-specific and functional. Furthermore, donor-matched iKCs and iPSC-hepatocyte co-culture exhibited minimal non-specific background response compared to donor-mismatched counterpart. iKCs offer a mature renewable human cell source for liver-specific macrophages, useful in developing in vitro model to study DILI and liver diseases such as cholestasis.