Highly Efficient Generation of Human Hepatocyte-like Cells from Induced Pluripotent Stem Cells

Overview

Journal Hepatology

Specialty Gastroenterology

Date 2009 Dec 10

PMID 19998274

Citations 589

Authors

Karim Si-Tayeb

Fallon K Noto

Masato Nagaoka

Jixuan Li

Michele A Battle

Christine Duris

Paula E North

Stephen Dalton

Stephen A Duncan

Affiliations

Soon will be listed here.

Abstract

Unlabelled: There exists a worldwide shortage of donor livers available for orthotropic liver transplantation and hepatocyte transplantation therapies. In addition to their therapeutic potential, primary human hepatocytes facilitate the study of molecular and genetic aspects of human hepatic disease and development and provide a platform for drug toxicity screens and identification of novel pharmaceuticals with potential to treat a wide array of metabolic diseases. The demand for human hepatocytes, therefore, heavily outweighs their availability. As an alternative to using donor livers as a source of primary hepatocytes, we explored the possibility of generating patient-specific human hepatocytes from induced pluripotent stem (iPS) cells.

Conclusion: We demonstrate that mouse iPS cells retain full potential for fetal liver development and describe a procedure that facilitates the efficient generation of highly differentiated human hepatocyte-like cells from iPS cells that display key liver functions and can integrate into the hepatic parenchyma in vivo.

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References

DAmour K, Agulnick A, Eliazer S, Kelly O, Kroon E, Baetge E . Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol. 2005; 23(12):1534-41. DOI: 10.1038/nbt1163. View

Gupta S, Chowdhury J . Therapeutic potential of hepatocyte transplantation. Semin Cell Dev Biol. 2002; 13(6):439-46. DOI: 10.1016/s1084952102001325. View

Grompe M . Principles of therapeutic liver repopulation. J Inherit Metab Dis. 2006; 29(2-3):421-5. DOI: 10.1007/s10545-006-0311-2. View

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K . Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131(5):861-72. DOI: 10.1016/j.cell.2007.11.019. View

Park I, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A . Disease-specific induced pluripotent stem cells. Cell. 2008; 134(5):877-86. PMC: 2633781. DOI: 10.1016/j.cell.2008.07.041. View

Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H . Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology. 2007; 45(5):1229-39. DOI: 10.1002/hep.21582. View

Mikkelsen T, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P . Dissecting direct reprogramming through integrative genomic analysis. Nature. 2008; 454(7200):49-55. PMC: 2754827. DOI: 10.1038/nature07056. View

Yu J, Vodyanik M, Smuga-Otto K, Antosiewicz-Bourget J, Frane J, Tian S . Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007; 318(5858):1917-20. DOI: 10.1126/science.1151526. View

Hay D, Fletcher J, Payne C, Terrace J, Gallagher R, Snoeys J . Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci U S A. 2008; 105(34):12301-6. PMC: 2518825. DOI: 10.1073/pnas.0806522105. View

10.

Jung J, Zheng M, Goldfarb M, Zaret K . Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science. 1999; 284(5422):1998-2003. DOI: 10.1126/science.284.5422.1998. View

11.

Park I, Zhao R, West J, Yabuuchi A, Huo H, Ince T . Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2007; 451(7175):141-6. DOI: 10.1038/nature06534. View

12.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

13.

Hay D, Zhao D, Fletcher J, Hewitt Z, McLean D, Urruticoechea-Uriguen A . Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo. Stem Cells. 2008; 26(4):894-902. DOI: 10.1634/stemcells.2007-0718. View

14.

Fisher R, Strom S . Human hepatocyte transplantation: worldwide results. Transplantation. 2006; 82(4):441-9. DOI: 10.1097/01.tp.0000231689.44266.ac. View

15.

Baharvand H, Hashemi S, Shahsavani M . Differentiation of human embryonic stem cells into functional hepatocyte-like cells in a serum-free adherent culture condition. Differentiation. 2008; 76(5):465-77. DOI: 10.1111/j.1432-0436.2007.00252.x. View

16.

Burlina A . Hepatocyte transplantation for inborn errors of metabolism. J Inherit Metab Dis. 2004; 27(3):373-83. DOI: 10.1023/B:BOLI.0000031095.57411.8d. View

17.

Muraca M, Gerunda G, Neri D, Granato A, Feltracco P, Meroni M . Hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet. 2002; 359(9303):317-8. DOI: 10.1016/S0140-6736(02)07529-3. View

18.

Khetani S, Bhatia S . Microscale culture of human liver cells for drug development. Nat Biotechnol. 2007; 26(1):120-6. DOI: 10.1038/nbt1361. View

19.

Cho C, Parashurama N, Park E, Suganuma K, Nahmias Y, Park J . Homogeneous differentiation of hepatocyte-like cells from embryonic stem cells: applications for the treatment of liver failure. FASEB J. 2007; 22(3):898-909. DOI: 10.1096/fj.06-7764com. View

20.

Baharvand H, Hashemi S, Kazemi Ashtiani S, Farrokhi A . Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int J Dev Biol. 2006; 50(7):645-52. DOI: 10.1387/ijdb.052072hb. View