Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders

Kristen J Brennand¹, M Carol Marchetto², Nissim Benvenisty³, Oliver Brüstle⁴, Allison Ebert⁵, Juan Carlos Izpisua Belmonte⁶, Ajamete Kaykas⁷, Madeline A Lancaster⁸, Frederick J Livesey⁹, Michael J McConnell¹⁰, Ronald D McKay¹¹, Eric M Morrow¹², Alysson R Muotri¹³, David M Panchision¹⁴, Lee L Rubin¹⁵, Akira Sawa¹⁶, Frank Soldner¹⁷, Hongjun Song¹⁸, Lorenz Studer¹⁹, Sally Temple²⁰, Flora M Vaccarino²¹, Jun Wu⁶, Pierre Vanderhaeghen²², Fred H Gage²³, Rudolf Jaenisch²⁴

Affiliations

¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
² Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, San Diego, CA 92037, USA.
³ Department of Genetics, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
⁴ Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn, Bonn 53127, Germany.
⁵ Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
⁶ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, San Diego, CA 92037, USA.
⁷ Department of Neurobiology, Novartis Institute for BioMedical Research, Inc., 100 Technology Square, Cambridge, MA 02139, USA.
⁸ Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
⁹ Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
¹⁰ Department of Biochemistry and Molecular Genetics, Center for Brain Immunology and Glia, University of Virginia School of Medicine, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
¹¹ Brain Development, Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA.
¹² Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 70 Ship Street, Providence, RI 02912, USA.
¹³ Department of Cellular & Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA.
¹⁴ Developmental Neurobiology Program, National Institute of Mental Health, 6001 Executive Boulevard, Bethesda, MD 20892, USA.
¹⁵ Department of Stem Cell and Regenerative Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
¹⁶ Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA.
¹⁷ Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
¹⁸ Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
¹⁹ Stem Cell and Tumor Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY 10021, USA.
²⁰ Neural Stem Cell Institute, One Discovery Drive, Rensselaer, NY 12144, USA.
²¹ Child Study Center, Yale University, 230 South Frontage Road, New Haven, CT 06520, USA.
²² Institute of Interdisciplinary Research (IRIBHM), University of Brussels ULB, 808, Route de Lennik, 1070 Brussels, Belgium.
²³ Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, San Diego, CA 92037, USA. Electronic address: fgage@salk.edu.
²⁴ Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: jaenisch@wi.mit.edu.

PMID: 26610635
PMCID: PMC4881284
DOI: 10.1016/j.stemcr.2015.10.011

Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders

Kristen J Brennand et al. Stem Cell Reports. 2015.

. 2015 Dec 8;5(6):933-945.

doi: 10.1016/j.stemcr.2015.10.011. Epub 2015 Nov 21.

Authors

Affiliations

¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
² Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, San Diego, CA 92037, USA.
³ Department of Genetics, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
⁴ Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn, Bonn 53127, Germany.
⁵ Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
⁶ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, San Diego, CA 92037, USA.
⁷ Department of Neurobiology, Novartis Institute for BioMedical Research, Inc., 100 Technology Square, Cambridge, MA 02139, USA.
⁸ Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
⁹ Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
¹⁰ Department of Biochemistry and Molecular Genetics, Center for Brain Immunology and Glia, University of Virginia School of Medicine, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
¹¹ Brain Development, Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA.
¹² Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 70 Ship Street, Providence, RI 02912, USA.
¹³ Department of Cellular & Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA.
¹⁴ Developmental Neurobiology Program, National Institute of Mental Health, 6001 Executive Boulevard, Bethesda, MD 20892, USA.
¹⁵ Department of Stem Cell and Regenerative Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
¹⁶ Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA.
¹⁷ Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
¹⁸ Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
¹⁹ Stem Cell and Tumor Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY 10021, USA.
²⁰ Neural Stem Cell Institute, One Discovery Drive, Rensselaer, NY 12144, USA.
²¹ Child Study Center, Yale University, 230 South Frontage Road, New Haven, CT 06520, USA.
²² Institute of Interdisciplinary Research (IRIBHM), University of Brussels ULB, 808, Route de Lennik, 1070 Brussels, Belgium.
²³ Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, San Diego, CA 92037, USA. Electronic address: fgage@salk.edu.
²⁴ Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: jaenisch@wi.mit.edu.

PMID: 26610635
PMCID: PMC4881284
DOI: 10.1016/j.stemcr.2015.10.011

Abstract

As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.

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Figures

**Figure 1**
Current Challenges for Creating Meaningful Patient-Specific In Vitro Models to Study Brain Disorders A critical limitation of the field at present is the inherent difficulty in accurately defining cell states, particularly concerning the temporal and regional identity of pluripotent cells, neurons, and glial cells. A next step for hiPSC-based models of brain disorders will be building neural complexity in vitro, incorporating cell types and 3D organization to achieve network- and circuit-level structures. As the level of cellular complexity increases, new dimensions of modeling will emerge, and modeling neurological diseases that have a more complex etiology will be accessible. An important caveat to hiPSC-based models is the possibility that epigenetic factors and somatic mosaicism may contribute to neurological and neuropsychiatric disease, risk factors that may be difficult to capture in reprogramming or accurately recapitulate in vitro differentiation. A critical next step, in order to enable the use of hiPSCs for drug discovery, will be improving the scalability and reproducibility of in vitro differentiations and functional assays.

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References

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Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders

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Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders

Authors

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Abstract

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