Abstract
The liver fulfils a plethora of vital functions and, due to their importance, liver dysfunction has life-threatening consequences. Liver disorders currently account for more than two million deaths annually worldwide and can be classified broadly into three groups, considering their onset and aetiology, as acute liver diseases, inherited metabolic disorders and chronic liver diseases. In the most advanced and severe forms leading to liver failure, liver transplantation is the only treatment available, which has many associated drawbacks, including a shortage of organ donors. Cell therapy via fully mature cell transplantation is an advantageous alternative that may be able to restore a damaged organ’s functionality or serve as a bridge until regeneration can occur. Pioneering work has shown that transplanting adult hepatocytes can support liver recovery. However, primary hepatocytes cannot be grown extensively in vitro as they rapidly lose their metabolic activity. Therefore, different cell sources are currently being tested as alternatives to primary cells. Human pluripotent stem cell-derived cells, chemically induced liver progenitors, or ‘liver’ organoids, hold great promise for developing new cell therapies for acute and chronic liver diseases. This Review focuses on the advantages and drawbacks of distinct cell sources and the relative strategies to address different therapeutic needs in distinct liver diseases.
Key points
The current increase in the number of patients with liver disorders around the world represents a major health care challenge worldwide, especially with liver transplantation being the only treatment for end-stage disease.
Cell therapy can provide a promising alternative for the treatment of liver disorders, as engraftment of hepatocytes in the damaged liver can restore missing hepatic functions.
Liver disorders can be divided into three categories (acute liver diseases, inherited metabolic disorders and chronic liver disease), with different requirements that should be considered in developing a cell therapy strategy.
Primary hepatocytes have been used successfully for cell therapy in the context of liver disease, but the difficulty of growing these cells in vitro hinders therapeutic applications.
Alternative cell sources are currently being explored for wider employment of cell therapy, including human pluripotent stem cell-derived hepatocytes, ‘liver’ organoids, chemically induced liver progenitors, macrophages and mesenchymal stem cells.
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Fig. 1: Animal models for the evaluation of cell therapy strategies against distinct liver disorders.
Fig. 2: Differential architecture of ‘liver’ organoids derived from primary hepatocytes or cholangiocytes.
Fig. 3: Potential cell sources for cell therapy applications in liver disorders.
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Acknowledgements
The laboratory of L.V. is funded by core grants from the BIH and Max Planck Institute for Molecular Genetics, the ERC advanced grant Fun-Chol, and the Einstein Foundation.
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Berlin Institute of Health, BIH Centre for Regenerative Therapies, Charité-Universitätsmedizin, Berlin, Germany
M. Carmen Ortuño-Costela & Ludovic Vallier
Max Planck Institute for Molecular Genetics, Berlin, Germany
M. Carmen Ortuño-Costela & Ludovic Vallier
University College London Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, London, UK
Massimo Pinzani
University of Pittsburgh Medical Center-Mediterranean Institute for Transplantation and Highly Specialized Therapies (UPMC-ISMETT), Palermo, Italy
Massimo Pinzani
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M.C.O.-C. researched data for the article. L.V. and M.P. contributed substantially to discussion of the content. L.V. and M.C.O.-C. wrote the article. All authors reviewed and/or edited the manuscript before submission.
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L.V. is a shareholder of bit.bio and Bilitech. Both companies developed cell-based therapies against liver diseases. M.P. is a cofounder, shareholder, and consultant for Engitix Therapeutics. M.C.O.-C. declares no competing interests.
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Ortuño-Costela, M.C., Pinzani, M. & Vallier, L. Cell therapy for liver disorders: past, present and future. Nat Rev Gastroenterol Hepatol (2025). https://doi.org/10.1038/s41575-025-01050-2
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Accepted:11 February 2025
Published:18 March 2025
DOI:https://doi.org/10.1038/s41575-025-01050-2
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