Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia.

Susanna Raitano, Laura Ordovàs, Louis De Muynck, Wenting Guo, Ira Espuny-Camacho, Martine Geraerts, Satish Khurana, Kim Vanuytsel, Balazs I Tóth, Thomas Voets, Rik Vandenberghe, Toni Cathomen, Ludo Van Den Bosch, Pierre Vanderhaeghen, Philip Van Damme, Catherine M Verfaillie

Journal: Stem cell reports 2015;4(1):16-24

PMID: 25556567

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Abstract

To understand how haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), we created induced pluripotent stem cells (iPSCs) from patients carrying the GRN(IVS1+5G > C) mutation (FTD-iPSCs). FTD-iPSCs were fated to cortical neurons, the cells most affected in FTD. Although generation of neuroprogenitors was unaffected, their further differentiation into CTIP2-, FOXP2-, or TBR1-TUJ1 double-positive cortical neurons, but not motorneurons, was significantly decreased in FTD-neural progeny. Zinc finger nuclease-mediated introduction of GRN cDNA into the AAVS1 locus corrected defects in cortical neurogenesis, demonstrating that PGRN haploinsufficiency causes inefficient cortical neuron generation. RNA sequencing analysis confirmed reversal of the altered gene expression profile following genetic correction. We identified the Wnt signaling pathway as one of the top defective pathways in FTD-iPSC-derived neurons, which was reversed following genetic correction. Differentiation of FTD-iPSCs in the presence of a WNT inhibitor mitigated defective corticogenesis. Therefore, we demonstrate that PGRN haploinsufficiency hampers corticogenesis in vitro.

Address: Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.; Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium.; Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium; Institute of Neuroscience (UNI), ULB, 1070 Brussels, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center of Human Genetics, KU Leuven, 3000 Leuven, Belgium.; Laboratory of Ion Channel Research, KU Leuven, 3000 Leuven, Belgium.; Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.; Institute for Cell and Gene Therapy, University Medical Center, 79108 Freiburg, Germany; Center for Chronic Immunodeficiency, University Medical Center, 79108 Freiburg, Germany.; Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium; Institute of Neuroscience (UNI), ULB, 1070 Brussels, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center of Human Genetics, KU Leuven, 3000 Leuven, Belgium; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1070 Brussels, Belgium.; Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.; Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium. Electronic address: [email protected].

DOI: 10.1016/j.stemcr.2014.12.001