Grantee Research Project Results

2018 Progress Report: Organotypic Liver Model for Predictive Human Toxicology and Metabolism

EPA Grant Number: R835736C004
Subproject: this is subproject number 004 , established and managed by the Center Director under grant R835736
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Mickey Leland National Urban Air Toxics Research Center (NUATRC)
Center Director: Beskid, Craig
Title: Organotypic Liver Model for Predictive Human Toxicology and Metabolism
Investigators: Taylor, D. Lansing , Davidson, Jeffrey M. , Gough, Albert , Vernetti, Lawrence
Institution: University of Pittsburgh , Vanderbilt University
EPA Project Officer: Aja, Hayley
Project Period: December 1, 2014 through November 30, 2018 (Extended to November 30, 2019)
Project Period Covered by this Report: December 1, 2017 through November 30,2018
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability

Objective:

In the final year 4, our VPROMPT center goals were focused on seven Milestones: six in the area of integration and one concerning validation of iPSC hepatocytes for inclusion in our OCM.

Progress Summary:

Much of our final year efforts were focused on coupling our Liver OCM to the OCMs from other projects. Multiple factors such as media, scaling, flow rate, hardware compatibility and other issues had to be addressed before this integration could take place. Our initial approach to integration was functional coupling (media is conditioned in the liver OCM, then used to perfuse another OCM). In order to prepare conditioned media for functional coupling, we have calculated by allometric scaling the appropriate amount of liver conditioned media to provide to the other project teams.

After the appropriate scaling was determined and validated, we worked with the other project teams to select relevant test compounds for OCM treatment. Drugs were chosen based upon availability of reference clinical data and distribution of liver activities (non-toxic, known toxic, metabolized). Compounds with cLogP ≤ 3 were selected to minimize issues of drug binding to PDMS. Treated and control liver conditioned media was prepared for 8 compounds and delivered to Projects 1,2,3, and 5 (Table 2). In preparation for physical integration, we have trained the Vanderbilt project teams to recapitulate our liver OCM. All protocols and SOPS for Liver OCM assembly and assays have been uploaded to the VPROMPT SharePoint site, reviewed and approved. All components are commercially available and detailed in the SOPs. When the other projects have finalized their OCMs, we will be available to consult on integration if needed.

One additional milestone involved the validation of iPSC hepatocytes. Matured iPSC-derived human hepatocytes were obtained from a collaborator in order to take advantage of his patented iPSC hepatocyte maturation methodology. The functionality of the iPSC hepatocytes was determined by testing a metabolism probe mixture for three specific isoforms of human Cytochrome P450 and two for glucuronidation. In that study, comparing iPSC derived human hepatocytes and a pool of 20 human donors of cryopreserved hepatocytes, functional biomarkers such as albumin and urea secretion were comparable, and the oxidative metabolism activity found in iPSC cells for Cyp -1A2, -3A4 and -2C9 were 85 - 123% of donor pool levels .

Future Activities:

We have concluded our activities and will not take part in the NCE year. We have provided the necessary protocols to transfer the liver module to Vanderbilt and will provide remote consultation if needed.

Journal Articles on this Report : 5 Displayed | Download in RIS Format

Publications Views
Other subproject views:	All 34 publications	10 publications in selected types	All 10 journal articles
Other center views:	All 169 publications	57 publications in selected types	All 56 journal articles

Publications
Type	Citation	Sub Project	Document Sources
Journal Article	Lee-Montiel FT, George SM, Gough AH, Sharma AD, Wu J, DeBiasio R, Vernetti LA, Taylor DL. “Control of oxygen tension recapitulates zone-specific functions in human liver microphysiology systems. Exp Biol Med 2017;242(16):1617-1632.	R835736C004 (2018)	Full-text from PubMed Abstract from PubMed Abstract: Sage Journals - Abstract Exit
Journal Article	Li X, George SM, Vernetti L, Gough AH, Taylor DL. A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX. Lab on a Chip 2018;21;18(17):2614-2631	R835736C004 (2018)	Abstract from PubMed Abstract: Abstract - Lab on a Chip HTML Exit
Journal Article	Vernetti LA, Senutovitch N, Boltz R, DeBiasio R, Shun TY, Gough A, Taylor DL. A human liver microphysiology platform for investigating physiology, drug safety, and disease models. Experimental Biology and Medicine 2016;241(1):101-114.	R835736 (2015) R835736 (2016) R835736 (2017) R835736C004 (2015) R835736C004 (2016) R835736C004 (2017) R835736C004 (2018)	Full-text from PubMed Abstract from PubMed Associated PubMed link Abstract: Sage Publications-Abstract Exit
Journal Article	Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (14 pp.).	R835736 (2017) R835736C004 (2018) R835738C002 (2017) R835738C005 (2017)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Scientific Reports-Full Text HTML Exit Abstract: Scientific Reports-Abstract Exit Other: Scientific Reports-Full Text PDF Exit
Journal Article	Vernetti LA, Vogt A, Gough A, Taylor DL. Evolution of experimental models of the liver to predict human drug hepatotoxicity and efficacy. Clinics in Liver Disease 2017;21(1):197-214.	R835736 (2015) R835736 (2016) R835736 (2017) R835736C004 (2017) R835736C004 (2018)	Abstract from PubMed Abstract: Clinics in Liver Disease-Abstract Exit Other: ScienceDirect-First Page Preview Exit

Relevant Websites:

Microphysiology Systems Database Exit

The Vanderbilt-Pittsburgh Resource for Organotypic Models for Predictive Toxicology (VPROMPT) Exit

Progress and Final Reports:

Original Abstract

Main Center Abstract and Reports:

R835736 Mickey Leland National Urban Air Toxics Research Center (NUATRC)

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R835736C001 Mammosphere Bioreactor For Life-Stage Specific Toxicology
R835736C002 Organotypic Culture Model to Analyze DevelopmentalLimbMalformationsResulting from Toxicant/Teratogen Exposure
R835736C003 Validating a fetal membrane on a chip model for characterizing reproductive toxicant exposure risks
R835736C004 Organotypic Liver Model for Predictive Human Toxicology and Metabolism
R835736C005 Systems Engineering & Analysis for Organotypic Culture Models

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.