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Mol Pharm. 2016 Jun 6;13(6):1947-57. doi: 10.1021/acs.molpharmaceut.6b00119. Epub 2016 May 24.

Functionally Enhanced Human Stem Cell Derived Hepatocytes in Galactosylated Cellulosic Sponges for Hepatotoxicity Testing.

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Institute of Bioengineering and Nanotechnology , #04-01, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
Preclinical Development and Safety, Asia Pacific, Janssen Research & Development , 999 South Pudong Road, Shanghai, 200120, China.
Department of Physiology, Yong Loo Lin School of Medicine, National University Health System , MD9-03-03, 2 Medical Drive, Singapore 117597, Singapore.
NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences, National University of Singapore , #05-01, 28 Medical Drive, Singapore 117576, Singapore.
Mechanobiology Institute, T-Laboratories , #05-01, 5A Engineering Drive 1, Singapore 117411, Singapore.
Singapore-MIT Alliance for Research and Technology , 3 Science Drive 2, S16-05-08, Singapore 117543, Singapore.
Department of Biological Engineering, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.


Pluripotent stem cell derived hepatocyte-like cells (hPSC-HLCs) are an attractive alternative to primary human hepatocytes (PHHs) used in applications ranging from therapeutics to drug safety testing studies. It would be critical to improve and maintain mature hepatocyte functions of the hPSC-HLCs, especially for long-term studies. If 3D culture systems were to be used for such purposes, it would be important that the system can support formation and maintenance of optimal-sized spheroids for long periods of time, and can also be directly deployed in liver drug testing assays. We report the use of 3-dimensional (3D) cellulosic scaffold system for the culture of hPSC-HLCs. The scaffold has a macroporous network which helps to control the formation and maintenance of the spheroids for weeks. Our results show that culturing hPSC-HLCs in 3D cellulosic scaffolds increases functionality, as demonstrated by improved urea production and hepatic marker expression. In addition, hPSC-HLCs in the scaffolds exhibit a more mature phenotype, as shown by enhanced cytochrome P450 activity and induction. This enables the system to show a higher sensitivity to hepatotoxicants and a higher degree of similarity to PHHs when compared to conventional 2D systems. These results suggest that 3D cellulosic scaffolds are ideal for the long-term cultures needed to mature hPSC-HLCs. The mature hPSC-HLCs with improved cellular function can be continually maintained in the scaffolds and directly used for hepatotoxicity assays, making this system highly attractive for drug testing applications.


hepatocytes; hepatotoxicity; scaffolds; stem cells

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