Journal ArticleDOI
Vascularized and functional human liver from an iPSC-derived organ bud transplant
Takanori Takebe,Keisuke Sekine,Masahiro Enomura,Hiroyuki Koike,Masaki Kimura,Takunori Ogaeri,Ran-Ran Zhang,Yasuharu Ueno,Yun-Wen Zheng,Naoto Koike,Shinsuke Aoyama,Yasuhisa Adachi,Hideki Taniguchi +12 more
TLDR
This is the first report demonstrating the generation of a functional human organ from pluripotent stem cells by transplantation of liver buds created in vitro (iPSC-LBs), and provides a promising new approach to study regenerative medicine.Abstract:
A critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from human induced pluripotent stem cells (iPSCs). Despite many reports describing functional cell differentiation, no studies have succeeded in generating a three-dimensional vascularized organ such as liver. Here we show the generation of vascularized and functional human liver from human iPSCs by transplantation of liver buds created in vitro (iPSC-LBs). Specified hepatic cells (immature endodermal cells destined to track the hepatic cell fate) self-organized into three-dimensional iPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells. Immunostaining and gene-expression analyses revealed a resemblance between in vitro grown iPSC-LBs and in vivo liver buds. Human vasculatures in iPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of iPSC-LBs into tissue resembling the adult liver. Highly metabolic iPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement. Furthermore, mesenteric transplantation of iPSC-LBs rescued the drug-induced lethal liver failure model. To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells. Although efforts must ensue to translate these techniques to treatments for patients, this proof-of-concept demonstration of organ-bud transplantation provides a promising new approach to study regenerative medicine.read more
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Modeling Development and Disease with Organoids
TL;DR: 3D culture technology allow embryonic and adult mammalian stem cells to exhibit their remarkable self-organizing properties, and the resulting organoids reflect key structural and functional properties of organs such as kidney, lung, gut, brain and retina, and hold promise to predict drug response in a personalized fashion.
Journal ArticleDOI
Organogenesis in a dish: modeling development and disease using organoid technologies.
TL;DR: These studies illustrated two key events in structural organization during organogenesis: cell sorting out and spatially restricted lineage commitment, which are recapitulated in organoids, which self-assemble to form the cellular organization of the organ itself.
Journal ArticleDOI
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.
Patricio Godoy,Nicola J. Hewitt,Ute Albrecht,Melvin E. Andersen,Nariman Ansari,Sudin Bhattacharya,Johannes G. Bode,Jennifer Bolleyn,Christoph Borner,J Böttger,Albert Braeuning,Robert A. Budinsky,Britta Burkhardt,Neil R. Cameron,Giovanni Camussi,Chong Su Cho,Yun Jaie Choi,J. Craig Rowlands,Uta Dahmen,Georg Damm,Olaf Dirsch,María Teresa Donato,Jian Dong,Steven Dooley,Dirk Drasdo,Dirk Drasdo,Dirk Drasdo,Rowena Eakins,Karine Sá Ferreira,Valentina Fonsato,Joanna Fraczek,Rolf Gebhardt,Andrew Gibson,Matthias Glanemann,Christopher E. Goldring,María José Gómez-Lechón,Geny M. M. Groothuis,Lena Gustavsson,Christelle Guyot,David Hallifax,Seddik Hammad,Adam S. Hayward,Dieter Häussinger,Claus Hellerbrand,Philip Hewitt,Stefan Hoehme,Hermann-Georg Holzhütter,J. Brian Houston,Jens Hrach,Kiyomi Ito,Hartmut Jaeschke,Verena Keitel,Jens M. Kelm,B. Kevin Park,Claus Kordes,Gerd A. Kullak-Ublick,Edward L. LeCluyse,Peng Lu,Jennifer Luebke-Wheeler,Anna Lutz,Daniel J. Maltman,Madlen Matz-Soja,Patrick D. McMullen,Irmgard Merfort,Simon Messner,Christoph Meyer,Jessica Mwinyi,Dean J. Naisbitt,Andreas K. Nussler,Peter Olinga,Francesco Pampaloni,Jingbo Pi,Linda J. Pluta,Stefan Przyborski,Anup Ramachandran,Vera Rogiers,Cliff Rowe,Celine Schelcher,Kathrin Schmich,Michael Schwarz,Bijay Singh,Ernst H. K. Stelzer,Bruno Stieger,Regina Stöber,Yuichi Sugiyama,Ciro Tetta,Wolfgang E. Thasler,Tamara Vanhaecke,Mathieu Vinken,Thomas S. Weiss,Agata Widera,Courtney G. Woods,Jinghai James Xu,Kathy Yarborough,Jan G. Hengstler +94 more
TL;DR: This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro and how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes.
Journal ArticleDOI
Generation of cerebral organoids from human pluripotent stem cells
TL;DR: A recently established protocol for generating 3D brain tissue, so-called cerebral organoids, which closely mimics the endogenous developmental program and has the potential to model later events such as neuronal maturation and survival.
Journal ArticleDOI
An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control
TL;DR: The widespread importance of Wnt signaling in driving tissue renewal has been revealed by the identification of Axin2 and Lgr5, genes expressed in cells that are responding to Wnt signals, and this crucial role in stem cell self renewal is reviewed.
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