NU 2016-110
Inventors
Jason Wertheim*
Bo Wang
Short Description
Novel iPCS-derived hepatocytes developed in 3-D microenvironment for biomedical research and drug discovery
Abstract
Induced pluripotent stem cells (iPSCs) are new diagnostic and potentially therapeutic tools to model disease and assess toxicity of pharmaceutical medications. A common, and critical, limitation of cell lineages derived from iPSCs is a blunted phenotype compared to fully-developed, endogenous cells. We found that three-dimensional bioartificial microenvironments made from liver derived extracellular matrix (ECM) increases function and maturation of hepatocyte-like cells differentiated from iPSCs and grown within an acellular, ECM-derived scaffolds. iPSC-derived hepatocytes remained viable within ECM scaffolds and became polarized and formed bile canaliculi-like structures. Specifically, iPSC-hepatocytes grown within ECM scaffolds had significantly higher P450 (CYP2C9, CYP3A4, CYP1A2) mRNA levels and metabolic enzyme activity compared to iPSC-hepatocytes grown in gold-standard Matrigel sandwich control culture. Additionally, the rate of albumin synthesis approached the level of primary cryopreserved hepatocytes with lower transcription of fetal-specific genes, alpha fetoprotein and CYP3A7, compared to gold-standard sandwich culture. These studies show that liver-derived ECM acellular scaffolds provide three-dimensional culture systems leading to increased function of iPSC-derived hepatocytes, and induce further hepatocyte maturation, helping to overcome a critical limitation in this field, suggesting their utility for in vitro hepatocyte assays, drug discovery, or other applications where mature, functional iPSC-derived cells are needed. The specific limitation is that cells derived from induced pluripotent cells (iPSCs) are uniformly immature and iPSC-derived hepatocytes have a blunted function compared to endogenous cells because of this limitation. We show that these scaffolds leads to 1) increased function and 2) increased maturity of iPSC-derived hepatocytes.
Applications
Advantages
Publications
Wang B, Jakus A, Baptista P, Soker S, Soto-Gutierrez A, Abecassis M, Shah R, Wertheim A (2016). Functional maturation of induced pluripotent stem cell hepatocytes in extracellular matrix-A comparative analysis of bioartificial liver microenvironments. Stem Cells Transl Med. 5(9): 1257-67.
IP Status
US Provisional patent application has been filed.