Abstract
The epilepsies and related disorders of brain circuitry present significant challenges associated with the use of human cells to study disease mechanisms and develop new therapies. Some of these obstacles are being overcome through the use of induced pluripotent stem cells to obtain patient-derived neural cells for in vitro studies and as a source of cell-based treatments. The field is evolving rapidly with the addition of genome-editing approaches and expanding protocols for generating different neural cell types and three-dimensional tissues, but the application of these techniques to neurological disorders, and particularly to the epilepsies, is in its infancy. We discuss the progress made and the distinct advantages and limitations of using patient-derived cells to study or treat epilepsy, as well as critical future directions for the field.
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References
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Thomson, J.A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Dimos, J.T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008).
Park, I.H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008).
Srikanth, P. & Young-Pearse, T.L. Stem cells on the brain: modeling neurodevelopmental and neurodegenerative diseases using human induced pluripotent stem cells. J. Neurogenet. 28, 5–29 (2014).
Paşca, S.P., Panagiotakos, G. & Dolmetsch, R.E. Generating human neurons in vitro and using them to understand neuropsychiatric disease. Annu. Rev. Neurosci. 37, 479–501 (2014).
Okano, H. & Yamanaka, S. iPS cell technologies: significance and applications to CNS regeneration and disease. Mol. Brain 7, 22 (2014).
Sandoe, J. & Eggan, K. Opportunities and challenges of pluripotent stem cell neurodegenerative disease models. Nat. Neurosci. 16, 780–789 (2013).
Lu, P. et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 83, 789–796 (2014).
Hargus, G. et al. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc. Natl. Acad. Sci. USA 107, 15921–15926 (2010).
Wang, S. et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12, 252–264 (2013).
Oki, K. et al. Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells 30, 1120–1133 (2012).
Chin, M.H. et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5, 111–123 (2009).
Guenther, M.G. et al. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7, 249–257 (2010).
Stadtfeld, M. & Hochedlinger, K. Induced pluripotency: history, mechanisms, and applications. Genes Dev. 24, 2239–2263 (2010).
Hanna, J.H., Saha, K. & Jaenisch, R. Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143, 508–525 (2010).
Loh, Y.H. et al. Generation of induced pluripotent stem cells from human blood. Blood 113, 5476–5479 (2009).
Seki, T. et al. Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7, 11–14 (2010).
Okita, K. et al. An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells 31, 458–466 (2013).
Fusaki, N., Ban, H., Nishiyama, A., Saeki, K. & Hasegawa, M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 85, 348–362 (2009).
Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801 (2009).
Müller, F.J. et al. A bioinformatic assay for pluripotency in human cells. Nat. Methods 8, 315–317 (2011).
Bock, C. et al. Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144, 439–452 (2011).
Theunissen, T.W. & Jaenisch, R. Molecular control of induced pluripotency. Cell Stem Cell 14, 720–734 (2014).
Morizane, A. et al. Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a nonhuman primate. Stem Cell Reports 1, 283–292 (2013).
Marchetto, M.C., Brennand, K.J., Boyer, L.F. & Gage, F.H. Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises. Hum. Mol. Genet. 20, R109–R115 (2011).
Chailangkarn, T., Acab, A. & Muotri, A.R. Modeling neurodevelopmental disorders using human neurons. Curr. Opin. Neurobiol. 22, 785–790 (2012).
Jang, J. et al. Induced pluripotent stem cells for modeling of pediatric neurological disorders. Biotechnol. J. 9, 871–881 (2014).
Wainger, B.J. et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 7, 1–11 (2014).
Lancaster, M.A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).
Brodie, M.J., Barry, S.J., Bamagous, G.A., Norrie, J.D. & Kwan, P. Patterns of treatment response in newly diagnosed epilepsy. Neurology 78, 1548–1554 (2012).
Miller, J.D. et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13, 691–705 (2013).
Mekhoubad, S. et al. Erosion of dosage compensation impacts human iPSC disease modeling. Cell Stem Cell 10, 595–609 (2012).
Tomoda, K. et al. Derivation conditions impact X-inactivation status in female human induced pluripotent stem cells. Cell Stem Cell 11, 91–99 (2012).
Zeng, H. et al. Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures. Cell 149, 483–496 (2012).
Wang, X., Tsai, J.W., LaMonica, B. & Kriegstein, A.R. A new subtype of progenitor cell in the mouse embryonic neocortex. Nat. Neurosci. 14, 555–561 (2011).
LaMonica, B.E., Lui, J.H., Wang, X. & Kriegstein, A.R. OSVZ progenitors in the human cortex: an updated perspective on neurodevelopmental disease. Curr. Opin. Neurobiol. 22, 747–753 (2012).
Shcheglovitov, A. et al. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503, 267–271 (2013).
Wang, X., Xu, Q., Bey, A.L., Lee, Y. & Jiang, Y.H. Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice. Mol. Autism 5, 30 (2014).
Yoon, K.J. et al. Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell 15, 79–91 (2014).
Dolce, A., Ben-Zeev, B., Naidu, S. & Kossoff, E.H. Rett syndrome and epilepsy: an update for child neurologists. Pediatr. Neurol. 48, 337–345 (2013).
Dajani, R., Koo, S.E., Sullivan, G.J. & Park, I.H. Investigation of Rett syndrome using pluripotent stem cells. J. Cell. Biochem. 114, 2446–2453 (2013).
Marchetto, M.C. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).
Cheung, A.Y. et al. Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum. Mol. Genet. 20, 2103–2115 (2011).
Ananiev, G., Williams, E.C., Li, H. & Chang, Q. Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. PLoS ONE 6, e25255 (2011).
Kim, K.Y., Hysolli, E. & Park, I.H. Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome. Proc. Natl. Acad. Sci. USA 108, 14169–14174 (2011).
Williams, E.C. et al. Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons. Hum. Mol. Genet. 23, 2968–2980 (2014).
Berry-Kravis, E. Epilepsy in fragile X syndrome. Dev. Med. Child Neurol. 44, 724–728 (2002).
Wang, T., Bray, S.M. & Warren, S.T. New perspectives on the biology of fragile X syndrome. Curr. Opin. Genet. Dev. 22, 256–263 (2012).
Eiges, R. et al. Establishment of human embryonic stem cell-transfected clones carrying a marker for undifferentiated cells. Curr. Biol. 11, 514–518 (2001).
Urbach, A., Bar-Nur, O., Daley, G.Q. & Benvenisty, N. Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6, 407–411 (2010).
Sheridan, S.D. et al. Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS ONE 6, e26203 (2011).
Liu, J. et al. Signaling defects in iPSC-derived fragile X premutation neurons. Hum. Mol. Genet. 21, 3795–3805 (2012).
Telias, M., Segal, M. & Ben-Yosef, D. Neural differentiation of Fragile X human embryonic stem cells reveals abnormal patterns of development despite successful neurogenesis. Dev. Biol. 374, 32–45 (2013).
Splawski, I. et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004).
Yazawa, M. et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471, 230–234 (2011).
Paşca, S.P. et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med. 17, 1657–1662 (2011).
Krey, J.F. et al. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat. Neurosci. 16, 201–209 (2013).
Marini, C. et al. The genetics of Dravet syndrome. Epilepsia 52 (suppl. 2), 24–29 (2011).
Ragona, F. et al. Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients. Epilepsia 52, 386–392 (2011).
Yu, F.H. et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat. Neurosci. 9, 1142–1149 (2006).
Ogiwara, I. et al. Na(v)1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J. Neurosci. 27, 5903–5914 (2007).
Higurashi, N. et al. A human Dravet syndrome model from patient induced pluripotent stem cells. Mol. Brain 6, 19 (2013).
Jiao, J. et al. Modeling Dravet syndrome using induced pluripotent stem cells (iPSCs) and directly converted neurons. Hum. Mol. Genet. 22, 4241–4252 (2013).
Liu, Y. et al. Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann. Neurol. 74, 128–139 (2013).
Mistry, A.M. et al. Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice. Neurobiol. Dis. 65, 1–11 (2014).
Leyser, M., Penna, P.S., de Almeida, A.C., Vasconcelos, M.M. & Nascimento, O.J. Revisiting epilepsy and the electroencephalogram patterns in Angelman syndrome. Neurol. Sci. 35, 701–705 (2014).
Williams, C.A., Driscoll, D.J. & Dagli, A.I. Clinical and genetic aspects of Angelman syndrome. Genet. Med. 12, 385–395 (2010).
Chamberlain, S.J. et al. Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes. Proc. Natl. Acad. Sci. USA 107, 17668–17673 (2010).
Ricciardi, S. et al. CDKL5 ensures excitatory synapse stability by reinforcing NGL-1–PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat. Cell Biol. 14, 911–923 (2012).
Livide, G. et al. GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells. Eur. J. Hum. Genet. (2014).
Southwell, D.G. et al. Interneurons from embryonic development to cell-based therapy. Science 344, 1240622 (2014).
Tyson, J.A. & Anderson, S.A. GABAergic interneuron transplants to study development and treat disease. Trends Neurosci. 37, 169–177 (2014).
Tanaka, D.H. & Nakajima, K. GABAergic interneuron migration and the evolution of the neocortex. Dev. Growth Differ. 54, 366–372 (2012).
Guo, J. & Anton, E.S. Decision making during interneuron migration in the developing cerebral cortex. Trends Cell Biol. 24, 342–351 (2014).
Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002).
Zecevic, N., Hu, F. & Jakovcevski, I. Interneurons in the developing human neocortex. Dev. Neurobiol. 71, 18–33 (2011).
Ma, T. et al. Subcortical origins of human and monkey neocortical interneurons. Nat. Neurosci. 16, 1588–1597 (2013).
Hansen, D.V. et al. Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences. Nat. Neurosci. 16, 1576–1587 (2013).
Wichterle, H., Garcia-Verdugo, J.M., Herrera, D.G. & Alvarez-Buylla, A. Young neurons from medial ganglionic eminence disperse in adult and embryonic brain. Nat. Neurosci. 2, 461–466 (1999).
Maroof, A.M., Brown, K., Shi, S.H., Studer, L. & Anderson, S.A. Prospective isolation of cortical interneuron precursors from mouse embryonic stem cells. J. Neurosci. 30, 4667–4675 (2010).
Danjo, T. et al. Subregional specification of embryonic stem cell-derived ventral telencephalic tissues by timed and combinatory treatment with extrinsic signals. J. Neurosci. 31, 1919–1933 (2011).
Au, E. et al. A modular gain-of-function approach to generate cortical interneuron subtypes from ES cells. Neuron 80, 1145–1158 (2013).
Maisano, X. et al. Differentiation and functional incorporation of embryonic stem cell-derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy. J. Neurosci. 32, 46–61 (2012).
Fertuzinhos, S. et al. Selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia. Cereb. Cortex 19, 2196–2207 (2009).
Maroof, A.M. et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12, 559–572 (2013).
Nicholas, C.R. et al. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12, 573–586 (2013).
Liu, Y. et al. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat. Biotechnol. 31, 440–447 (2013).
Kim, T.G. et al. Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation. Stem Cells 32, 1789–1804 (2014).
Cunningham, M. et al. hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice. Cell Stem Cell 15, 559–573 (2014).
Alvarez-Dolado, M. et al. Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain. J. Neurosci. 26, 7380–7389 (2006).
Zipancic, I., Calcagnotto, M.E., Piquer-Gil, M., Mello, L.E. & Alvarez-Dolado, M. Transplant of GABAergic precursors restores hippocampal inhibitory function in a mouse model of seizure susceptibility. Cell Transplant. 19, 549–564 (2010).
Vierbuchen, T. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).
Ring, K.L. et al. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell 11, 100–109 (2012).
Kim, H.S., Bernitz, J., Lee, D.F. & Lemischka, I.R. Genomic editing tools to model human diseases with isogenic pluripotent stem cells. Stem Cells Dev. 23, 2673–2686 (2014).
Halai, R. & Cooper, M.A. Using label-free screening technology to improve efficiency in drug discovery. Expert Opin. Drug Discov. 7, 123–131 (2012).
Yu, D.X. et al. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Reports 2, 295–310 (2014).
Chen, C. et al. Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells. Nat. Commun. 5, 4430 (2014).
Acknowledgements
The authors thank L. Isom and S. Barmada for comments on the manuscript; X. Du, G. Patino and Y. Liu for providing data for the figures; and the US National Institutes of Health (grants NS065450 and NS076916 to J.M.P. and grant MH066912 to S.A.A.) and Citizens United for Research in Epilepsy (to J.M.P.) for financial support.
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Parent, J., Anderson, S. Reprogramming patient-derived cells to study the epilepsies. Nat Neurosci 18, 360–366 (2015). https://doi.org/10.1038/nn.3944
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DOI: https://doi.org/10.1038/nn.3944
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