title: Humanized mice with ectopic artificial liver tissues.
abstract: "Humanized" mice offer a window into aspects of human physiology that are otherwise inaccessible. The best available methods for liver humanization rely on cell transplantation into immunodeficient mice with liver injury but these methods have not gained widespread use due to the duration and variability of hepatocyte repopulation. In light of the significant progress that has been achieved in clinical cell transplantation through tissue engineering, we sought to develop a humanized mouse model based on the facile and ectopic implantation of a tissue-engineered human liver. These human ectopic artificial livers (HEALs) stabilize the function of cryopreserved primary human hepatocytes through juxtacrine and paracrine signals in polymeric scaffolds. In contrast to current methods, HEALs can be efficiently established in immunocompetent mice with normal liver function. Mice transplanted with HEALs exhibit humanized liver functions persistent for weeks, including synthesis of human proteins, human drug metabolism, drug-drug interaction, and drug-induced liver injury. Here, mice with HEALs are used to predict the disproportionate metabolism and toxicity of "major" human metabolites using multiple routes of administration and monitoring. These advances may enable manufacturing of reproducible in vivo models for diverse drug development and research applications.
authors: Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors: Alice A
authors: AA
authors: Chen
authors: David K
authors: DK
authors: Thomas
authors: Luvena L
authors: LL
authors: Ong
authors: Robert E
authors: RE
authors: Schwartz
authors: Todd R
authors: TR
authors: Golub
authors: Sangeeta N
authors: SN
authors: Bhatia
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D003374:Coumarins; D005453:Fluorescence; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000166:cytology*; D016031:Liver Transplantation / Q000379:methods*; D051379:Mice; D023822:Tissue Engineering / Q000379:methods*; D055114:X-Ray Microtomography
chemical_list: D003374:Coumarins; C030123:coumarin