Generating liver and pancreatic tissues from human iPS cells for regenerative medicine through understanding of the mechanisms of organ development.
Developing liver and pancreatic tissues from iPSC
Development of systems to prepare functional cells and tissues of sufficient quality and quantity is central to realization of stem cell-based therapy, drug screening and regenerative medicine. The liver is a central organ for metabolism and detoxification in the body and hence is one of the major targets for those applications. For the last two decades, our lab has been studying the molecular and cellular mechanisms underlying development of the liver, taking advantage of our originally developed methods to isolate and culture each type of liver omponent cells. During the course of liver organogenesis, parenchymal hepatocytes develop from fetal liver progenitor cells, also known as hepatoblasts, through multiple modes of cell–cell interactions with other types of non-arenchymal cell populations including endothelial cells and mesenchymal cells. Based on our accumulated knowledge and expertise on the mechanistic basis of the liver development, we have successfully established culture systems to achieve directed differentiation of functional hepatocytes, as well as other non-parenchymal cells, from human induced pluripotent stem cells (iPSCs) through corresponding progenitor cell populations. Further application of three-dimensional co-culture system have rendered those iPSC-derived liver cells to cooperatively organize functional liver tissues with remarkable metabolic activities. Similarly, we have also developed a culture system to generate pancreatic islet-like tissue structures containing insulin-producing β cells from human iPSCs. We are currently applying those iPSC-derived cells and tissues for regenerative medicine, drug discovery and disease
- Saijou E, Enomoto Y, Matsuda M, Yuet-Yin Kok C, Akira S, Tanaka M, Miyajima A. Neutrophils alleviate fibrosis in the CCl(4)-induced mouse chronic liver injury model. Hepatol Commun. 2018 Apr 12;2(6):703-717. doi: 10.1002/hep4.1178.
- Enomoto Y, Takagi R, Naito Y, Kiniwa T, Tanaka Y, Hamada-Tsutsumi S, Kawano M, Matsushita S, Ochiya T, Miyajima A. Identification of the novel 3' UTR sequences of human IL-21 mRNA as potential targets of miRNAs. Sci Rep. 2017 Aug 10;7(1):7780. doi: 10.1038/s41598-017-07853-x.
- Koui Y, Kido T, Ito T, Oyama H, Chen SW, Katou Y, Shirahige K, Miyajima A. An in vitro human liver model by iPSC-derived parenchymal and non-parenchymal cells. Stem Cell Reports. 2017 Aug 8;9(2):490-498. doi: 10.1016/j.stemcr.2017.06.010.
- Kido T, Koui Y, Suzuki K, Kobayashi A, Miura Y, Chern EY, Tanaka M, Miyajima A. CPM is a useful cell surface marker to isolate expandable bi-potential liver progenitor cells derived from human iPS cells. Stem Cell Reports. 2015 Oct 13;5(4):508-15. doi: 10.1016/j.stemcr.2015.08.008.
- Miyajima A, Tanaka M, Itoh T. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell. 2014 May1;14(5):561-74. doi: 10.1016/j.stem.2014.04.010.
- Saito H, Takeuchi M, Chida K, Miyajima A. Generation of glucose-responsive functional islets with a three-dimensional structure from mouse fetal pancreatic cells and iPS cells in vitro. PLoS One. 2011;6(12):e28209. doi: 10.1371/journal.pone.0028209.
- Tanimizu N, Nishikawa M, Saito H, Tsujimura T, Miyajima A. Isolation of hepatoblasts based on the expression of Dlk/Pref-1. J Cell Sci. 2003 May 1;116(Pt 9):1775-86.
- Kamiya A, Kinoshita T, Ito Y, Matsui T, Morikawa Y, Senba E, Nakashima K, Taga T, Yoshida K, Kishimoto T, Miyajima A. Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J. 1999 Apr 15;18(8):2127-36.
Project Associate Professor