Zonal heterogeneity in hepatic functions is well established both in vivo and in vitro, and is an important feature of the liver with implications fr zonal drug toxicity. However, how various factor gradients within the liver interact to modulate zonal hepatic functions in the human liver, and what role liver stromal cells play in such modulation are not well understood. Due to significant species-specific differences in liver functions, inducing and studying factors that regulate zonation in primary human liver cells is critical to elucidate similarities and differences with their animal counterparts for enabling a continuum of in vitro and in vivo investigations. However, in vitro models of human liver zonation are lacking, especially those that evaluate the long-term effects of factor gradients and stromal interactions on zonal functions in primary human hepatocytes. In order to address the aforementioned gap in knowledge, here we propose to investigate the effects of liver- relevant factor gradients and liver stromal cells on long-term functions of primary human hepatocytes in culture. We will utilize microfluidics to enable minimal use of limited primary human liver cells, and create independent, complex and overlapping gradients of soluble gradients onto multicellular liver cultures. We will assess the effects of gradients (O2, hormones) generated by our device on liver functions thought to be zonated in vivo, in the presence or absence of liver stromal cells. Results in vitro will be compared to mechanisms known in vivo. Ultimately, creating approaches and design rules for making a heterogeneous and stable population of human liver cells will allow recapitulation of this important liver feature in systems designed for drug screening, clinical use (i.e. bioartificial liver devices), and stem cell differentiation.

Public Health Relevance

Zonal heterogeneity in hepatic functions is an important feature of the liver;however, how various factor gradients modulate zonal hepatic functions in the human liver, and what role liver stromal cells play in such modulation is not well understood. This project will utilize microfluidics technology to investigate the effects of liver-relevant facor gradients and liver stromal cells on zonal functions of primary human hepatocytes in culture. Creating approaches and design rules for making a heterogeneous and stable population of human liver cells will allow recapitulation of this important liver feature in systems designed for drug screening, clinical use (i.e. bioartificial liver devices), and stem cell differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Small Research Grants (R03)
Project #
1R03EB019184-01
Application #
8773296
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hunziker, Rosemarie
Project Start
2014-09-22
Project End
2016-06-30
Budget Start
2014-09-22
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$81,719
Indirect Cost
$23,731
Name
Colorado State University-Fort Collins
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80521