iPS cell technologies: significance and applications to CNS regeneration and disease

In 2006, we demonstrated that mature somatic cells can be reprogrammed to a pluripotent state by gene transfer, generating induced pluripotent stem (iPS) cells. Since that time, there has been an enormous increase in interest regarding the application of iPS cell technologies to medical science, in particular for regenerative medicine and human disease modeling. In this review article, we outline the current status of applications of iPS technology to cell therapies (particularly for spinal cord injury), as well as neurological disease-specific iPS cell research (particularly for Parkinson’s disease and Alzheimer’s disease). Finally, future directions of iPS cell research are discussed including a) development of an accurate assay system for disease-associated phenotypes, b) demonstration of causative relationships between genotypes and phenotypes by genome editing, c) application to sporadic and common diseases, and d) application to preemptive medicine.

[1]  Nobutaka Hattori,et al.  PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy , 2012, Scientific Reports.

[2]  H. Weintraub,et al.  Expression of a single transfected cDNA converts fibroblasts to myoblasts , 1987, Cell.

[3]  G. Pellegrini,et al.  Long-Term Stability and Safety of Transgenic Cultured Epidermal Stem Cells in Gene Therapy of Junctional Epidermolysis Bullosa , 2013, Stem cell reports.

[4]  H. Okano,et al.  Generation of Stratified Squamous Epithelial Progenitor Cells from Mouse Induced Pluripotent Stem Cells , 2011, PloS one.

[5]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[6]  T. Shimazaki,et al.  Requirement for COUP-TFI and II in the temporal specification of neural stem cells in CNS development , 2008, Nature Neuroscience.

[7]  A. Koizumi,et al.  Spatiotemporal Recapitulation of Central Nervous System Development by Murine Embryonic Stem Cell‐Derived Neural Stem/Progenitor Cells , 2008, Stem cells.

[8]  Elo Leung,et al.  A TALE nuclease architecture for efficient genome editing , 2011, Nature Biotechnology.

[9]  J. Mertens,et al.  Excitation-induced ataxin-3 aggregation in neurons from patients with Machado–Joseph disease , 2011, Nature.

[10]  S. Tsuji.  Genetics of neurodegenerative diseases: insights from high-throughput resequencing , 2010, Human molecular genetics.

[11]  H. Okano,et al.  Olfactory cells via nasal biopsy reflect the developing brain in gene expression profiles: Utility and limitation of the surrogate tissues in research for brain disorders , 2013, Neuroscience Research.

[12]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[13]  H. Okano,et al.  Transplantation of in vitro‐expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats , 2002, Journal of neuroscience research.

[14]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[15]  C. Klein,et al.  Impact of recent genetic findings in Parkinson's disease , 2007, Current opinion in neurology.

[16]  L. Laurent,et al.  Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA⋅TTC triplet repeat instability. , 2010, Cell stem cell.

[17]  I. Wilmut,et al.  "Viable Offspring Derived from Fetal and Adult Mammalian Cells" (1997), by Ian Wilmut et al. , 2014 .

[18]  K. Garber.  Inducing translation , 2013, Nature Biotechnology.

[19]  C. Mummery,et al.  From Stealing Fire to Cellular Reprogramming: A Scientific History Leading to the 2012 Nobel Prize , 2013, Stem cell reports.

[20]  J. Keith Joung,et al.  High frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells , 2013, Nature Biotechnology.

[21]  Fred H. Gage,et al.  Modelling schizophrenia using human induced pluripotent stem cells , 2011, Nature.

[22]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[23]  Fabienne C. Fiesel,et al.  PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1 , 2010, Nature Cell Biology.

[24]  Y. Hoki,et al.  Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells , 2013, Nature.

[25]  Takashi Daimon,et al.  Feasibility, Safety, and Therapeutic Efficacy of Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Sheets in a Porcine Ischemic Cardiomyopathy Model , 2012, Circulation.

[26]  B. Doble,et al.  The ground state of embryonic stem cell self-renewal , 2008, Nature.

[27]  Satoshi Nishimura,et al.  Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells. , 2014, Cell stem cell.

[28]  G. Martin,et al.  Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. Viale,et al.  Modeling Pathogenesis and Treatment of Familial Dysautonomia using Patient Specific iPSCs , 2009, Nature.

[30]  A. Toyoda,et al.  Mutations for Gaucher disease confer high susceptibility to Parkinson disease. , 2009, Archives of neurology.

[31]  Ji Young Kim,et al.  Induced pluripotent stem cell models from X‐linked adrenoleukodystrophy patients , 2011, Annals of neurology.

[32]  Patrick A. Lewis,et al.  Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus , 2011, Nature communications.

[33]  F. Gage,et al.  Modeling brain disease in a dish: really? , 2012, Cell stem cell.

[34]  Kristopher L. Nazor,et al.  Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells , 2012, Nature.

[35]  H. Okano,et al.  Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue , 2012, Molecular Brain.

[36]  G. Daley,et al.  Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. , 2010, Cell stem cell.

[37]  M. Yamato,et al.  Generation of Corneal Epithelial Cells from Induced Pluripotent Stem Cells Derived from Human Dermal Fibroblast and Corneal Limbal Epithelium , 2012, PloS one.

[38]  Jan Gründemann,et al.  Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase , 2006, Nature Genetics.

[39]  D. Krainc,et al.  Mitochondrial Parkin Recruitment Is Impaired in Neurons Derived from Mutant PINK1 Induced Pluripotent Stem Cells , 2011, The Journal of Neuroscience.

[40]  A. Brice,et al.  What genetics tells us about the causes and mechanisms of Parkinson's disease. , 2011, Physiological reviews.

[41]  Feng Zhang,et al.  Genome engineering using CRISPR-Cas9 system. , 2015, Methods in molecular biology.

[42]  N. Ghebranious,et al.  Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology , 2005, Nucleic acids research.

[43]  Robert C. Thompson,et al.  The More, the Better: Modeling Dravet Syndrome With Induced Pluripotent Stem Cell-Derived Neurons , 2014 .

[44]  J. Mertens,et al.  APP Processing in Human Pluripotent Stem Cell-Derived Neurons Is Resistant to NSAID-Based γ-Secretase Modulation , 2013, Stem cell reports.

[45]  L. Forno,et al.  Neuropathology of Parkinson's Disease , 1996, Journal of neuropathology and experimental neurology.

[46]  Shinsei Minoshima,et al.  Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase , 2000, Nature Genetics.

[47]  Katsuhiro Yoshikawa,et al.  Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. , 2013, Cell stem cell.

[48]  C. Svendsen,et al.  Induced pluripotent stem cells: a new revolution for clinical neurology? , 2011, The Lancet Neurology.

[49]  H. Okano,et al.  Modeling human neurological disorders with induced pluripotent stem cells , 2014, Journal of neurochemistry.

[50]  Junichi Kiryu,et al.  Characterization of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cell Sheets Aiming for Clinical Application , 2014, Stem cell reports.

[51]  D. Balota,et al.  Clinical and psychological characteristics of the initial cohort of the Dominantly Inherited Alzheimer Network (DIAN). , 2014, Neuropsychology.

[52]  Hideyuki Okano,et al.  Pre-Evaluated Safe Human iPSC-Derived Neural Stem Cells Promote Functional Recovery after Spinal Cord Injury in Common Marmoset without Tumorigenicity , 2012, PloS one.

[53]  Daniel T. Montoro,et al.  Characterization of Human Huntington's Disease Cell Model from Induced Pluripotent Stem Cells , 2010, PLoS currents.

[54]  J. Gurdon,et al.  The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. , 1962, Journal of embryology and experimental morphology.

[55]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[56]  H. Okano,et al.  Enhanced Aggregation of Androgen Receptor in Induced Pluripotent Stem Cell-derived Neurons from Spinal and Bulbar Muscular Atrophy* , 2013, The Journal of Biological Chemistry.

[57]  K. Kasai,et al.  Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia , 2014, Neuron.

[58]  Keiichiro Suzuki,et al.  Efficient and accurate homologous recombination in hESCs and hiPSCs using helper-dependent adenoviral vectors. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[59]  K. Sekiguchi,et al.  Isolation of Human Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors by Cell Sorting for Successful Transplantation , 2014, Stem cell reports.

[60]  Torsten Kluba,et al.  Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. , 2013, Cell stem cell.

[61]  H. Okano,et al.  A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord , 2006, Nature Medicine.

[62]  K. Nabeshima,et al.  A human Dravet syndrome model from patient induced pluripotent stem cells , 2013, Molecular Brain.

[63]  K. Mikoshiba,et al.  Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. , 1996, Developmental biology.

[64]  John K. Heath,et al.  Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides , 1988, Nature.

[65]  Hideyuki Okano,et al.  Steps Toward Safe Cell Therapy Using Induced Pluripotent Stem Cells , 2013, Circulation research.

[66]  H. Onoe,et al.  Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson's disease. , 2011, Journal of Parkinson's disease.

[67]  H. Okano,et al.  Fibroblast growth factor‐2/brain‐derived neurotrophic factor—associated maturation of new neurons generated from adult human subependymal cells , 1998, Annals of neurology.

[68]  Blake Byers,et al.  LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. , 2011, Cell stem cell.

[69]  H. Hioki,et al.  Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells , 2012, Science Translational Medicine.

[70]  Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury , 2013, Molecular Brain.

[71]  S. Mastana,et al.  Genetic Variation of Apolipoproteins in North Indians , 2002, Human biology.

[72]  H. Okano,et al.  Modeling familial Alzheimer's disease with induced pluripotent stem cells. , 2011, Human molecular genetics.

[73]  Nicholas G Martin,et al.  Toward the development of a global induced pluripotent stem cell library. , 2013, Cell stem cell.

[74]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[75]  Randall J Bateman,et al.  Dominantly Inherited Alzheimer Network: facilitating research and clinical trials , 2013, Alzheimer's Research & Therapy.

[76]  S. Yamanaka,et al.  Transient activation of c-MYC expression is critical for efficient platelet generation from human induced pluripotent stem cells , 2010, The Journal of experimental medicine.

[77]  H. Okano,et al.  Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells , 2012, Cell Research.

[78]  R A Crowther,et al.  Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. , 1998, Neuroscience letters.

[79]  S. Yuasa,et al.  Induced Pluripotent Stem Cells in Cardiovascular Medicine , 2011, Stem cells international.

[80]  D. Krainc,et al.  Human iPSC-based modeling of late-onset disease via progerin-induced aging. , 2013, Cell stem cell.

[81]  MasashiKawamura,et al.  Feasibility, Safety, and Therapeutic Efficacy of Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Sheets in a Porcine Ischemic Cardiomyopathy Model , 2012 .

[82]  S. Yamanaka.  Induced pluripotent stem cells: past, present, and future. , 2012, Cell stem cell.

[83]  H. Okano,et al.  Grafted human-induced pluripotent stem-cell–derived neurospheres promote motor functional recovery after spinal cord injury in mice , 2011, Proceedings of the National Academy of Sciences.

[84]  Fred H. Gage,et al.  A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells , 2010, Cell.

[85]  H. Okano,et al.  Transplantation of human neural stem cells for spinal cord injury in primates , 2005, Journal of neuroscience research.

[86]  Hynek Wichterle,et al.  Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons , 2008, Science.

[87]  Yang Xu,et al.  Immunogenicity of induced pluripotent stem cells , 2011, Nature.

[88]  C. E. Pearson,et al.  Huntington's and myotonic dystrophy hESCs: down-regulated trinucleotide repeat instability and mismatch repair machinery expression upon differentiation. , 2011, Human molecular genetics.

[89]  E. Bouhassira,et al.  Zinc-finger nuclease-mediated correction of α-thalassemia in iPS cells. , 2012, Blood.

[90]  David A. Scott,et al.  Double Nicking by RNA-Guided CRISPR Cas9 for Enhanced Genome Editing Specificity , 2013, Cell.

[91]  H. Okano,et al.  Functional corneal endothelium derived from corneal stroma stem cells of neural crest origin by retinoic acid and Wnt/β-catenin signaling. , 2013, Stem cells and development.

[92]  A. Muotri,et al.  Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients , 2011, Human molecular genetics.

[93]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[94]  Hideyuki Okano,et al.  Variation in the safety of induced pluripotent stem cell lines , 2009, Nature Biotechnology.

[95]  Nigel J. Cairns,et al.  Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies , 1998, Neuroscience Letters.

[96]  Hideyuki Okano,et al.  Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury , 2010, Proceedings of the National Academy of Sciences.

[97]  T. Iwatsubo,et al.  Disease‐modifying therapy for Alzheimer's disease: Challenges and hopes , 2013 .

[98]  Norio Nakatsuji,et al.  Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells , 2001, Current Biology.

[99]  Jiao Jiao,et al.  Modeling Dravet syndrome using induced pluripotent stem cells (iPSCs) and directly converted neurons. , 2013, Human molecular genetics.

[100]  Shinya Yamanaka,et al.  Immunogenicity of induced pluripotent stem cells. , 2011, Circulation research.

[101]  James A. Thomson,et al.  Induced pluripotent stem cells from a spinal muscular atrophy patient , 2009, Nature.

[102]  M. Elisaf,et al.  Apolipoprotein E and renal disease. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[103]  Andrew J. Saykin,et al.  The pattern of atrophy in familial Alzheimer disease , 2013, Neurology.