Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells
S. Tamir Rashid,Sébastien Corbineau,Nicholas R.F. Hannan,Stefan J. Marciniak,Elena Miranda,Graeme J.M. Alexander,Isabel Huang-Doran,Julian L. Griffin,Lars Ährlund-Richter,Jeremy N. Skepper,Robert K. Semple,Anne Weber,David A. Lomas,Ludovic Vallier +13 more
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TLDR
These patient-derived hepatocytes demonstrate that it is possible to model diseases whose phenotypes are caused by pathological dysregulation of key processes within adult cells, and a simple and effective platform for hepatocyte generation from patient-specific human iPS cells.Abstract:
Human induced pluripotent stem (iPS) cells hold great promise for advancements in developmental biology, cell-based therapy, and modeling of human disease. Here, we examined the use of human iPS cells for modeling inherited metabolic disorders of the liver. Dermal fibroblasts from patients with various inherited metabolic diseases of the liver were used to generate a library of patient-specific human iPS cell lines. Each line was differentiated into hepatocytes using what we believe to be a novel 3-step differentiation protocol in chemically defined conditions. The resulting cells exhibited properties of mature hepatocytes, such as albumin secretion and cytochrome P450 metabolism. Moreover, cells generated from patients with 3 of the inherited metabolic conditions studied in further detail (α1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease type 1a) were found to recapitulate key pathological features of the diseases affecting the patients from which they were derived, such as aggregation of misfolded α1-antitrypsin in the endoplasmic reticulum, deficient LDL receptor–mediated cholesterol uptake, and elevated lipid and glycogen accumulation. Therefore, we report a simple and effective platform for hepatocyte generation from patient-specific human iPS cells. These patient-derived hepatocytes demonstrate that it is possible to model diseases whose phenotypes are caused by pathological dysregulation of key processes within adult cells.read more
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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.
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Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver
Meritxell Huch,Helmuth Gehart,Ruben van Boxtel,Karien Hamer,Francis Blokzijl,Monique M A Verstegen,Ewa Ellis,Martien van Wenum,Sabine A. Fuchs,Joep de Ligt,Marc van de Wetering,Nobuo Sasaki,Susanne J. Boers,Hans Kemperman,Jeroen de Jonge,Jan N. M. IJzermans,Edward E. S. Nieuwenhuis,Ruurdtje Hoekstra,Stephen C. Strom,Robert R G Vries,Luc J. W. van der Laan,Edwin Cuppen,Hans Clevers +22 more
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Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses
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Generation of Isogenic Pluripotent Stem Cells Differing Exclusively at Two Early Onset Parkinson Point Mutations
Frank Soldner,Josee Laganiere,Albert W. Cheng,Dirk Hockemeyer,Qing Gao,Raaji Alagappan,Vikram Khurana,Vikram Khurana,Lawrence I. Golbe,Richard H. Myers,Susan Lindquist,Lei Zhang,Dmitry Guschin,Lauren K. Fong,B. Joseph Vu,Xiangdong Meng,Fyodor D. Urnov,Edward J. Rebar,Philip D. Gregory,H. Steve Zhang,Rudolf Jaenisch +20 more
TL;DR: In this article, the authors proposed to generate sets of isogenic disease and control human pluripotent stem cells that differ exclusively at either of two susceptibility variants for Parkinson's disease by modifying the underlying point mutations in the α-synuclein gene.
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Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells
Kosuke Yusa,S. Tamir Rashid,Helene Strick-Marchand,Helene Strick-Marchand,Ignacio Varela,Pei-Qi Liu,David Paschon,Elena Miranda,Elena Miranda,Adriana Ordóñez,Nicholas R.F. Hannan,Foad J. Rouhani,Foad J. Rouhani,Sylvie Darche,Sylvie Darche,Graeme J.M. Alexander,Stefan J. Marciniak,Noemi Fusaki,Mamoru Hasegawa,Michael C. Holmes,James P. Di Santo,James P. Di Santo,David A. Lomas,Allan Bradley,Ludovic Vallier +24 more
TL;DR: This work shows that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation in the α1-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α1
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