Researchers developed a new strategy that could improve induced pluripotent stem cell (iPSC)-derived hepatocyte-like cell engraftment in alpha-1 antitrypsin deficiency (AATD). The study will be presented at the 2022 The Liver Meeting.

“We established a safe way to transiently express hepatocyte growth factor (HGF) and epidermal growth factor (EGF) specifically in the liver using nonintegrative nucleoside-modified mRNA encapsulated in lipid nanoparticles,” the researchers explained.

They found that this strategy allowed for a transient improvement of iPSC-derived hepatocyte-like cell survival in a mouse model of AATD liver disease (NSG-PiZ mice).

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In addition, they showed that HGF and EGF mRNA-lipid nanoparticle treatment promoted transplanted primary human hepatocyte survival and proliferation in NSG-PiZ mice. These mice showed an increased number of primary human hepatocyte clusters, as well as an increased number of cells per cluster compared with control mice. Moreover, they had more proliferating primary human hepatocytes and a higher total percentage of primary human hepatocyte repopulation. The researchers also observed increased levels of human serum albumin in NSG-PiZ mice treated with HGF and EGF mRNA-lipid nanoparticle compared with control mice.

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The induction of p21 expression in HGF and EGF mRNA-lipid nanoparticle-treated mice further enhanced the effects observed, suggesting that it could be an additional approach to potentiate hepatocyte survival and proliferation in AATD. The researchers used an AAV8-TBG-p21 viral vector to achieve long-lasting, hepatocyte-specific expression of the cell cycle inhibitor p21 in the host mouse liver, thereby blocking host hepatocyte proliferation.

iPSCs from patients with AATD can be genetically manipulated and corrected, providing a virtually unlimited source of healthy hepatocyte-like cells for transplantation. However, poor survival, proliferation, and maturation of transplanted cells could dictate the failure of hepatocyte-like cell engraftment. Strategies to support survival and proliferation of such cells are vital to improve cell therapy in AATD.


Smith A, Rizvi F, Everton E, et al. Primary hepatocyte and iPSC-derived hepatocyte-like cell transplantation to treat alpha-1 antitrypsin deficiency associated liver disease. Hepatology. 2022;76(S1):S137-S138.