Engineering Human iPSC-Derived Livers in Rats for Advanced Liver Disease Treatment

Researchers at the University of Pittsburgh have developed a novel method for engineering human induced pluripotent stem cell-derived livers (iPSC-Heps) in rats. This innovative approach addresses the critical shortage of donor livers for transplantation by providing a reliable source of functional hepatocytes. The technology has the potential to revolutionize the treatment of liver diseases by enabling the generation of patient-specific liver cells for autologous transplantation and disease modeling.

Schematic of the Workflow for liver repopulation in immune-compromised rats using human iPS-heps.

Description

The invention involves an efficient hepatic differentiation protocol that produces iPSC-Heps with a relatively mature phenotype. These cells are capable of repopulating the livers of immune-compromised rats, demonstrating their functionality and potential for clinical applications. The method also includes engineering human iPS cells with a doxycycline-inducible Cas9 or shRNA system, allowing for targeted gene editing and regulation after transplantation. This approach ensures the production of iPSC-Heps with functions and regeneration responsiveness identical to normal adult hepatocytes, making it a valuable tool for treating liver failure.

Applications

• Autologous liver cell transplantation
• Disease modeling and research
• Treatment of liver-based inborn errors of metabolism
• Regenerative medicine and liver tissue engineering

Advantages

This technology offers several key advantages: it provides an inexhaustible supply of functional liver cells from autologous tissue, eliminates the need for lifelong immunosuppressive drugs, and enables early intervention in patients with hepatic failure. The ability to generate patient-specific hepatocytes in an in vivo bioreactor derived from iPS cells represents a significant advancement in liver disease treatment and research.

Invention Readiness

The technology is currently at the in vivo data stage, with successful proof-of-concept studies demonstrating the ability of iPSC-Heps to repopulate rat livers. Initial experiments have shown that these cells can engraft and functionally replace liver tissue in immune-compromised rats. The research team is focused on further refining the hepatic differentiation protocol and conducting preclinical testing to validate the technology's efficacy and safety.

IP Status

https://patents.google.com/patent/WO2018152120A1

Related Publication(s)

Takeishi, K., Collin de l’Hortet, A., Wang, Y., Handa, K., Guzman-Lepe, J., Matsubara, K., Morita, K., Jang, S., Haep, N., Florentino, R. M., Yuan, F., Fukumitsu, K., Tobita, K., Sun, W., Franks, J., Delgado, E. R., Shapiro, E. M., Fraunhoffer, N. A., Duncan, A. W., … Soto-Gutierrez, A. (2020). Assembly and Function of a Bioengineered Human Liver for Transplantation Generated Solely from Induced Pluripotent Stem Cells. Cell Reports, 31(9), 107711. https://doi.org/10.1016/j.celrep.2020.107711