Liver cell therapies: cellular sources and grafting strategies

Abstract

The liver has a complex cellular composition and a remarkable regenerative capacity. The primary cell types in the liver are two parenchymal cell populations, hepatocytes and cholangiocytes, that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells, endothelia and various hemopoietic cell populations. The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates, the extracellular matrix, working synergistically with soluble paracrine and systemic signals. In recent years, with the rapid development of genetic sequencing technologies, research on the liver’s cellular composition and its regulatory mechanisms during various conditions has been extensively explored. Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases, offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation. This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair. Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.

Keywords

liver regeneration / hepatocytes / cholangiocytes / stem cells / organoids / regulatory mechanisms / transplantation/grafting strategies

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Acknowledgements

This work was funded by Major Program of National Key Research and Development Project (Nos. 2020YFA0112600 and 2019YFA0801502), National Natural Science Foundation of China (Nos. 82173019, 82270638, and 82203741), Shanghai Pujiang Program (No. 21PJD059), the Project of Shanghai Science and Technology Commission (Nos. 22ZR1451100, 19140902900, and 22Y11908500), Program of Shanghai Academic/Technology Research Leader (No. 20XD1434000), Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai, Jiangxi Provincial Natural Science Foundation (No. 20212ACB206033), and Shanghai Engineering Research Center of Stem Cells Translational Medicine (No. 20DZ2255100).

Lola M. Reid and her associates and their studies were funded by Vesta Therapeutics (Bethesda, MD), an NIH grant (HL051587) awarded to J. Piedrahita (NCSU, Raleigh, NC), funding from the UNC School of Medicine, the Fibrolamellar Carcinoma Foundation (Greenwich, CT) and by multiple NIH Core and Center grants (5P41EB002025); Center for Gastrointestinal and Biliary Disease Biology (NIDDK Grant: P30 DK034987); and the Lineberger Cancer Center grant (NCI grant # CA016086).

The authors kindly thank Professor Giacomo Lanzoni of the Miller School of Medicine of University of Miami, and Dr. Diletta Overi and Professors Guido Carpino, Alvaro Domenico, Eugenio Gaudio from the Sapienza University of Rome for providing suggestions for revisions.

Compliance with ethics guidelines

Wencheng Zhang, Yangyang Cui, Yuan Du, Yong Yang, Ting Fang, Fengfeng Lu, Weixia Kong, Canjun Xiao, Jun Shi, Lola M. Reid, and Zhiying He declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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