# A Novel Stem Cell-based Approach for Generating Non-Human Primate Livers in Pigs

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $548,335

## Abstract

Project Summary/Abstract
At present there are more than 30,000 patients waiting to receive liver transplants. The number is increasing
due to an aging US population accompanied by an increasing incidence of chronic liver diseases associated
with such disorders as alcoholic liver disease, hepatitis, NAFLD and NASH. In spite of efforts to persuade
people to serve as organ donors, the demand increasingly outstrips the supply for organ transplantation. One
solution to this problem is the ability to generate human livers in animals for liver as well as hepatocyte
transplantation. Although there are numerous protocols to differentiate human embryonic stem cells (hESCs),
and inducible pluripotent stem cells (iPSCs) ex vivo to a variety of cell types, they have encountered significant
challenges in translation to the clinic. However, it is now possible to regenerate the replica of organs/cells from
one species of animal within the body of a second species. This involves the knockout (KO) of specific
developmental genes in the blastocyst of species two; and the intra-blastocyst injection of pluripotent stem
cells from species one to generate offspring that carry organs/cell types derived from that donor. The
translation of this approach requires an efficient gene-editing technology. In fact, novel TALEN/CRISPR/Cas9
technologies provide such a rapid, and cost-effective means to generate genetically modified animals.
Accordingly, we propose to employ the TALEN/CRISPR technology to knockout specific genes associated with
liver development in the pig blastocyst. We hypothesize that non-human primate liver can be generated in the
pig by the injection of marmoset embryonic stem cells (ESCs) into TALEN and/or CRISPR-KO porcine
blastocysts. Marmosets are often used for research on human aging and disease because their bodies are
very close to those of humans. We have designed three Specific Aims to test our central hypothesis.
Specifically, we will (1) generate pig-pig liver chimeras by blastocyst complementation as proof-of-principle; (2)
develop marmoset livers in a model of non-human primate-pig chimeras in addition to characterizing their
functionality; and (3) interrogate the genetic programs involved in generating human-porcine chimeric livers.
The generation of whole livers that are comprised primarily of non-human primate hepatic cells derived from
implanted marmoset ESCs would represent a paradigm shift and provide the necessary preclinical evidence
for ultimately creating human livers in animals. If successful, the proposed research would be a game-changer
that could conceivably pave the way for the production of human livers in large animals, such as the pig, for
organ and/or hepatocyte transplantation that is specifically tailored for each patient suffering from a chronic
liver disease. In addition, this novel, albeit somewhat high-risk approach circumvents many of the problems
associated with decades of research on xenotransplantation. The potential ...

## Key facts

- **NIH application ID:** 9886244
- **Project number:** 5R01DK117286-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** CLIFFORD John STEER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $548,335
- **Award type:** 5
- **Project period:** 2018-04-02 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886244

## Citation

> US National Institutes of Health, RePORTER application 9886244, A Novel Stem Cell-based Approach for Generating Non-Human Primate Livers in Pigs (5R01DK117286-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9886244. Licensed CC0.

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