4294

Method to Differentiate Metabolically Functional Human Hepatocytes from Pluripotent Stem Cells

Nahmias Yaakov, HUJI, School of Computer Science and Engineering, Bio-Engineering

Category

LifeSciences and BioTechnology   

 

Application

Primary human hepatocytes are isolated from organs rejected from transplantation. Cells are expensive, show massive batch-to-batch variability and fail to proliferate in culture. Hepatocytes are routinely used by the pharmaceutical industry for drug development and toxicological studies.

Human pluripotent stem cell-derived hepatocytes offer a solution due to their minimal variability, high repeatability and lower costs. However, current stem cell-derived hepatocytes show immature fetal function (e.g. AFP), minimal drug metabolism and marginal correlation of toxicity compared to primary cells (R2=0.19).

 

Our Innovation

Our patent-protected methods shows:

  • 90% hepatocytes in 16-18 days
  • Double mitochondrial mass and energetic, rather than glycolytic function
  • CYP450 induction up to 80-fold on mRNA level (3A4, 1A2, 2B1)
  • Accurate toxic evaluation of steatosis and cholestasis
  • Strong correlation of toxicity compared to primary hepatocytes (R2=0.94)

 

Technology

We discovered the last step in human liver development and used it to create the first truly functional pluripotent stem cell-derived hepatocytes. Our method and protocol has been validated by several groups. The technology can be used to create a kit that allows the pharmaceutical industry to produce cells from their own cell lines, or to produce stem cell-derived hepatocytes to sell as frozen aliquots.

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Opportunity

Human pluripotent stem cell-derived hepatocytes offer a solution due to their minimal variability, high repeatability, lower costs. However, current stem cell-derived hepatocytes show immature fetal function (e.g. AFP), minimal drug metabolism and marginal correlation of toxicity compared to primary cells (R2=0.19).

Our method produces truly functional pluripotent stem cell-derived hepatocytes. The cells show minimal fetal markers (e.g. AFP, CYP3A7), strong 80-fold CYP450 induction in response to Rifampicin, CITCO and Omeprazole, and toxicological screening values comparable to primary hepatocytes with minimal variability.

 

Y. Avior, G. Levy, M. Zimerman D. Kitsberg, R. Schwartz, R. Sadeh, A. Moussaieff, M. Cohen, J. Itskovitz-Eldor, Y. Nahmias. Microbial-Derived Lithocholic Acid and Vitamin K2 Drive the Metabolic Maturation of Pluripotent Stem Cells Derived Hepatocytes. Hepatology 2(1): 265-78. (2015)

 

A. Ehrlich, M. Ayyash, S. Tsytkin, G. Levy, M. Zimerman, R. Schwartz, M. Cohen, Y. Nahmias. Microbial-Derived Fatty Acids Drive the Mitochondrial Maturation of Pluripotent Stem Cells-Derived and Fetal Hepatocytes. Submitted for publication

Contact for more information:

Mel Larrosa
VP Business Development Healthcare
+972-2-6586692
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