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Review
. 2018 Apr;154(5):1258-1272.
doi: 10.1053/j.gastro.2018.01.066. Epub 2018 Feb 8.

Biotechnology Challenges to In Vitro Maturation of Hepatic Stem Cells

Chen Chen  1 , Alejandro Soto-Gutierrez  2 , Pedro M Baptista  3 , Bart Spee  4
Affiliations
Review

Biotechnology Challenges to In Vitro Maturation of Hepatic Stem Cells

Chen Chen et al. Gastroenterology. 2018 Apr.

Abstract

The incidence of liver disease is increasing globally. The only curative therapy for severe end-stage liver disease, liver transplantation, is limited by the shortage of organ donors. In vitro models of liver physiology have been developed and new technologies and approaches are progressing rapidly. Stem cells might be used as a source of liver tissue for development of models, therapies, and tissue-engineering applications. However, we have been unable to generate and maintain stable and mature adult liver cells ex vivo. We review factors that promote hepatocyte differentiation and maturation, including growth factors, transcription factors, microRNAs, small molecules, and the microenvironment. We discuss how the hepatic circulation, microbiome, and nutrition affect liver function, and the criteria for considering cells derived from stem cells to be fully mature hepatocytes. We explain the challenges to cell transplantation and consider future technologies for use in hepatic stem cell maturation, including 3-dimensional biofabrication and genome modification.

Keywords: Culture; Differentiation; Hepatocyte; Liver Development.

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Conflict of interest statement

Conflicts of interest

This author discloses the following: A.S.-G. has a provisional patent application that describes hepatic differentiation of human pluripotent stem cells and liver repopulation. A.S.-G. is a co-founder and has a financial interest in Von Baer Wolff, Inc, a company focused on biofabrication of autologous human hepatocytes from stem cells technology. A.S.-G.’s interests are managed by the Conflict of Interest Office at the University of Pittsburgh in accordance with their policies. The remaining authors disclose no conflicts.

Figures

Figure 1.
Figure 1.
Changes in liver maturation from fetus to newborn. Upon birth, the human fetal liver undergoes many changes, including changes in circulation, the microbiome, and nutrition, which are required for hepatic maturation. Increasing our understanding of these changes might provide information needed to develop more efficient in vitro liver maturation methods.
Figure 2.
Figure 2.
Cells and methods to generate HLCs. Blue boxes show cells, and yellow and pink boxes show methods, used to generate HLCs.
Figure 3.
Figure 3.
Molecular changes during hepatocyte differentiation. Transcription factors and signaling molecules that regulate each stage of hepatocyte differentiation. Hepatocyte-generating cells are colored and supporting tissue are black and gray. Question marks indicate pathways under investigation.
Figure 4.
Figure 4.
Small molecules that generate HLCs or promote HLC maturation. Several small molecules can promote differentiation of HPCs and MSCs into HLCs. DNMTis prime differentiation of MSCs into HLCs. HDACis act during or after differentiation into HLCs. DAPT and A8301 block differentiation of HPCs into cholangiocytes.
Figure 5.
Figure 5.
Structural, metabolic, and secretory functions of mature hepatocytes. Mature hepatocytes have a typical epithelial cell structure, including polygonal shape and presence of epithelial markers, highly express genes related to drug metabolism (phase 1, 2, and 3), secrete albumin, and produce urea and bile acid.
See this image and copyright information in PMC

References

    1. Kim WR, Therneau TM, Benson JT, et al. Deaths on the liver transplant waiting list: an analysis of competing risks. Hepatology 2006;43:345–351. - PubMed
    1. Soldatow VY, LeCluyse EL, Griffith LG, et al. In vitro models for liver toxicity testing. Toxicol Res 2013;2: 23–39. - PMC - PubMed
    1. Guidotti JE, Bregerie O, Robert A, et al. Liver cell polyploidization: a pivotal role for binuclear hepatocytes. J Biol Chem 2003;278:19095–19101. - PubMed
    1. Gentric G, Desdouets C. Polyploidization in liver tissue. Am J Pathol 2014;184:322–331. - PubMed
    1. Zaret KS. From endoderm to liver bud: paradigms of cell type specification and tissue morphogenesis. Curr Top Dev Biol 2016;117:647–669. - PubMed

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