Technical challenges in using human induced pluripotent stem cells to model disease.

Reprogramming of human somatic cells uses readily accessible tissue, such as skin or blood, to generate embryonic-like induced pluripotent stem cells (iPSCs). This procedure has been applied to somatic cells from patients who are classified into a disease group, thus creating "disease-specific" iPSCs. Here, we examine the challenges and assumptions in creating a disease model from a single cell of the patient. Both the kinetics of disease onset and progression as well as the spatial localization of disease in the patient's body are challenges to disease modeling. New tools in genetic modification, reprogramming, biomaterials, and animal models can be used for addressing these challenges.

[1]  Stefan Grimm,et al.  The art and design of genetic screens: mammalian culture cells , 2004, Nature Reviews Genetics.

[2]  J. Gearhart New Potential for Human Embryonic Stem Cells , 1998, Science.

[3]  Jeroen S. van Zon,et al.  Direct cell reprogramming is a stochastic process amenable to acceleration , 2009, Nature.

[4]  Kristopher L. Nazor,et al.  Adult mice generated from induced pluripotent stem cells , 2009, Nature.

[5]  R. Jaenisch,et al.  A drug-inducible system for direct reprogramming of human somatic cells to pluripotency. , 2008, Cell stem cell.

[6]  N. Kneteman,et al.  Mice with chimeric human livers: Who says supermodels have to be tall? , 2005, Hepatology.

[7]  J. Rossant,et al.  Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency , 2009, Nature Methods.

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

[9]  Robert Lanza,et al.  Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. , 2009, Cell stem cell.

[10]  George Q. Daley,et al.  Reprogramming of human somatic cells to pluripotency with defined factors , 2008, Nature.

[11]  G. Keller,et al.  Identification and targeting of the ROSA26 locus in human embryonic stem cells , 2007, Nature Biotechnology.

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

[13]  Alessandra Giorgetti,et al.  Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. , 2009, Cell stem cell.

[14]  Xiaolei Yin,et al.  Two supporting factors greatly improve the efficiency of human iPSC generation. , 2008, Cell stem cell.

[15]  J. C. Belmonte,et al.  Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector , 2009, Proceedings of the National Academy of Sciences.

[16]  Chad A. Cowan,et al.  A high-efficiency system for the generation and study of human induced pluripotent stem cells. , 2008, Cell stem cell.

[17]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[18]  Shinya Yamanaka,et al.  Induced Pluripotent Stem Cells , 2011, SpringerBriefs in Stem Cells.

[19]  N. Socci,et al.  BAC Transgenesis in Human Embryonic Stem Cells as a Novel Tool to Define the Human Neural Lineage , 2009, Stem cells.

[20]  K. Plath,et al.  Generation of human induced pluripotent stem cells from dermal fibroblasts , 2008, Proceedings of the National Academy of Sciences.

[21]  Sheng Ding,et al.  A chemical approach to stem-cell biology and regenerative medicine , 2008, Nature.

[22]  R. Jaenisch,et al.  Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease , 2008, Proceedings of the National Academy of Sciences.

[23]  R. Crystal,et al.  Genetic control of wayward pluripotent stem cells and their progeny after transplantation. , 2009, Cell stem cell.

[24]  Nobuko Uchida,et al.  Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R. Stewart,et al.  Human Induced Pluripotent Stem Cells Free of Vector and Transgene Sequences , 2009, Science.

[26]  Hideki Uosaki,et al.  Directed and Systematic Differentiation of Cardiovascular Cells From Mouse Induced Pluripotent Stem Cells , 2008, Circulation.

[27]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells From Adult Human Fibroblasts by Defined Factors , 2008 .

[28]  Luigi Naldini,et al.  Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery , 2007, Nature Biotechnology.

[29]  R. Bronson,et al.  A mouse model for Down syndrome exhibits learning and behaviour deficits , 1995, Nature Genetics.

[30]  Prashant Mali,et al.  Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. , 2009, Cell stem cell.

[31]  F. Guilak,et al.  Control of stem cell fate by physical interactions with the extracellular matrix. , 2009, Cell stem cell.

[32]  O. Yanuka,et al.  Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos. , 2007, Cell stem cell.

[33]  A. Trounson,et al.  Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro , 2000, Nature Biotechnology.

[34]  K. Akashi,et al.  Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. , 2005, Blood.

[35]  Qi Zhou,et al.  iPS cells produce viable mice through tetraploid complementation , 2009, Nature.

[36]  G. Daley,et al.  Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells , 2009, Nature Biotechnology.

[37]  Wei Wang,et al.  piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells , 2009, Nature.

[38]  T. Schoeb,et al.  Polycistronic Lentiviral Vector for “Hit and Run” Reprogramming of Adult Skin Fibroblasts to Induced Pluripotent Stem Cells , 2009, Stem cells.

[39]  Peter R Braude,et al.  Generation of a human embryonic stem cell line encoding the cystic fibrosis mutation deltaF508, using preimplantation genetic diagnosis. , 2005, Reproductive biomedicine online.

[40]  Peter G Schultz,et al.  Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4 , 2009, Proceedings of the National Academy of Sciences.

[41]  M. Kotb,et al.  Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells 12 , 2004, The Journal of Immunology.

[42]  Y. Sasai,et al.  In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction , 2009, Journal of Cell Science.

[43]  J. Thomson,et al.  Hematopoietic and Endothelial Differentiation of Human Induced Pluripotent Stem Cells , 2009, Stem cells.

[44]  Alan Colman,et al.  Pluripotent stem cells and disease modeling. , 2009, Cell stem cell.

[45]  M. Tomishima,et al.  Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling , 2009, Nature Biotechnology.

[46]  James A. Thomson,et al.  Homologous recombination in human embryonic stem cells , 2003, Nature Biotechnology.

[47]  M. Schuldiner,et al.  Modeling for Lesch‐Nyhan Disease by Gene Targeting in Human Embryonic Stem Cells , 2004, Stem cells.

[48]  Tim Morris,et al.  Physiological Parameters in Laboratory Animals and Humans , 1993, Pharmaceutical Research.

[49]  L. Fugger,et al.  Humanized mouse models for organ-specific autoimmune diseases. , 2006, Current opinion in immunology.

[50]  R. Jaenisch,et al.  Functional characterization of cardiomyocytes derived from murine induced pluripotent stem cells in vitro , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[51]  Peter W Zandstra,et al.  Alternative induced pluripotent stem cell characterization criteria for in vitro applications. , 2009, Cell stem cell.

[52]  A. Consiglio,et al.  Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes , 2008, Nature Biotechnology.

[53]  P. Devroey,et al.  Derivation of human embryonic stem cell lines from embryos obtained after IVF and after PGD for monogenic disorders. , 2006, Human reproduction.

[54]  K. Woltjen,et al.  New strategies to generate induced pluripotent stem cells. , 2009, Current opinion in biotechnology.

[55]  H. Schöler,et al.  In vitro differentiation of reprogrammed murine somatic cells into hepatic precursor cells , 2008, Biological chemistry.

[56]  Shulan Tian,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[57]  Mike J. Mason,et al.  Role of the Murine Reprogramming Factors in the Induction of Pluripotency , 2009, Cell.

[58]  K. Eggan,et al.  Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. , 2008, Cell stem cell.

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

[60]  Shaorong Gao,et al.  Cell Stem Cell Brief Report Ips Cells Can Support Full-term Development of Tetraploid Blastocyst-complemented Embryos Cell Stem Cell Brief Report , 2022 .

[61]  Dale L. Greiner,et al.  Humanized mice in translational biomedical research , 2007, Nature Reviews Immunology.

[62]  R. Behringer Human-animal chimeras in biomedical research. , 2007, Cell stem cell.

[63]  U. Lendahl,et al.  Regenerative medicine: a 2009 overview , 2009, Journal of internal medicine.

[64]  C. McKerlie,et al.  Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia , 1996, Nature Genetics.

[65]  Martin Pera,et al.  A method for genetic modification of human embryonic stem cells using electroporation , 2007, Nature Protocols.

[66]  Robin Goland,et al.  Generation of pluripotent stem cells from patients with type 1 diabetes , 2009, Proceedings of the National Academy of Sciences.

[67]  B. Kaspar,et al.  Two Factor Reprogramming of Human Neural Stem Cells into Pluripotency , 2009, PloS one.

[68]  Deepak M. Gupta,et al.  Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells , 2009, Proceedings of the National Academy of Sciences.

[69]  Wenjun Guo,et al.  Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds , 2008, Nature Biotechnology.

[70]  E. Stanley,et al.  Targeting a GFP reporter gene to the MIXL1 locus of human embryonic stem cells identifies human primitive streak-like cells and enables isolation of primitive hematopoietic precursors. , 2008, Blood.

[71]  M. Hasegawa,et al.  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 , 2009, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[72]  T. Mikkelsen,et al.  Dissecting direct reprogramming through integrative genomic analysis , 2008, Nature.

[73]  A. Consiglio,et al.  Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells , 2009, Nature.

[74]  I Wilmut,et al.  Induced pluripotent stem cells: epigenetic memories and practical implications. , 2010, Molecular human reproduction.

[75]  T. Prolla,et al.  Evolution of the Aging Brain Transcriptome and Synaptic Regulation , 2008, PloS one.

[76]  A. Trounson,et al.  Genetic modification of human embryonic stem cells for derivation of target cells. , 2008, Cell stem cell.

[77]  H. Schöler,et al.  A combined chemical and genetic approach for the generation of induced pluripotent stem cells. , 2008, Cell stem cell.

[78]  L. Rubin Stem Cells and Drug Discovery: The Beginning of a New Era? , 2008, Cell.

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

[80]  Kenneth M. Yamada,et al.  Modeling Tissue Morphogenesis and Cancer in 3D , 2007, Cell.

[81]  Dong Wook Han,et al.  Generation of induced pluripotent stem cells using recombinant proteins. , 2009, Cell stem cell.

[82]  Stefan Wagner,et al.  Generation of induced pluripotent stem cells from human cord blood. , 2009, Cell stem cell.

[83]  K. Woltjen,et al.  Virus free induction of pluripotency and subsequent excision of reprogramming factors , 2009, Nature.

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

[85]  C. Mummery,et al.  Prospects for pluripotent stem cell‐derived cardiomyocytes in cardiac cell therapy and as disease models , 2009, Journal of cellular biochemistry.

[86]  H. Okano,et al.  Adipogenic differentiation of human induced pluripotent stem cells: Comparison with that of human embryonic stem cells , 2009, FEBS letters.

[87]  K. Sermon,et al.  Recurrent chromosomal abnormalities in human embryonic stem cells , 2008, Nature Biotechnology.

[88]  F. Gage,et al.  Development of functional human embryonic stem cell-derived neurons in mouse brain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[89]  B. Stockwell Exploring biology with small organic molecules , 2004, Nature.

[90]  F. Gage,et al.  Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. , 2008, Cell stem cell.

[91]  M. Kotb,et al.  Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells 12 , 2004, The Journal of Immunology.

[92]  S. Gruber,et al.  Further Commentary: Physiological Parameters in Laboratory Animals and Humans , 1994, Pharmaceutical Research.

[93]  C. Dang,et al.  Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. , 2009, Blood.

[94]  Daniel G. Anderson,et al.  Nanoparticles for gene transfer to human embryonic stem cell colonies. , 2008, Nano letters.

[95]  T. Cantz,et al.  Induced pluripotent stem cells generated without viral integration , 2009, Hepatology.

[96]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[97]  A. Brivanlou,et al.  An efficient and reversible transposable system for gene delivery and lineage-specific differentiation in human embryonic stem cells. , 2009, Cell stem cell.

[98]  R. Gibbs,et al.  The Critical Region in Trisomy 21 , 2004, Science.

[99]  George Q. Daley,et al.  Disease-Specific Induced Pluripotent Stem Cells , 2008, Cell.

[100]  L. Fink,et al.  Phenotypic correction of murine hemophilia A using an iPS cell-based therapy , 2009, Proceedings of the National Academy of Sciences.

[101]  L. Allen Stem cells. , 2003, The New England journal of medicine.

[102]  B. Davidson,et al.  Infection efficiency of human and mouse embryonic stem cells using adenoviral and adeno-associated viral vectors. , 2003, Cloning and stem cells.

[103]  Shinya Yamanaka,et al.  Generation of Mouse Induced Pluripotent Stem Cells Without Viral Vectors , 2008, Science.

[104]  Su-Chun Zhang,et al.  Transgenes delivered by lentiviral vector are suppressed in human embryonic stem cells in a promoter-dependent manner. , 2007, Stem cells and development.

[105]  Eric S. Lander,et al.  Dissecting direct reprogramming through integrative genomic analysis , 2008, Nature.

[106]  K. Plath,et al.  Reprogrammed Mouse Fibroblasts Differentiate into Cells of the Cardiovascular and Hematopoietic Lineages , 2008, Stem cells.

[107]  Shinya Yamanaka,et al.  Broader implications of defining standards for the pluripotency of iPSCs. , 2009, Cell stem cell.

[108]  N. Socci,et al.  High-throughput screening assay for the identification of compounds regulating self-renewal and differentiation in human embryonic stem cells. , 2008, Cell stem cell.

[109]  Anne E Carpenter,et al.  A Lentiviral RNAi Library for Human and Mouse Genes Applied to an Arrayed Viral High-Content Screen , 2006, Cell.

[110]  Nobuko Uchida,et al.  Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI , 2007, Proceedings of the National Academy of Sciences.

[111]  George Q. Daley,et al.  Prospects for Stem Cell-Based Therapy , 2008, Cell.

[112]  K. Akashi,et al.  Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice , 2005 .

[113]  Hidenori Akutsu,et al.  A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. , 2009, Cell stem cell.

[114]  Takashi Aoi,et al.  Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts , 2008, Nature Biotechnology.

[115]  R. Jaenisch,et al.  Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases , 2009, Nature Biotechnology.

[116]  R. Jaenisch,et al.  Reprogramming of murine and human somatic cells using a single polycistronic vector , 2009, Proceedings of the National Academy of Sciences.

[117]  J. Utikal,et al.  Induced Pluripotent Stem Cells Generated Without Viral Integration , 2008, Science.

[118]  Marius Wernig,et al.  Treatment of Sickle Cell Anemia Mouse Model with iPS Cells Generated from Autologous Skin , 2007, Science.

[119]  Y. Kan,et al.  Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases , 2009, Proceedings of the National Academy of Sciences.

[120]  Jehyuk Lee,et al.  Generation of functional human hepatic endoderm from human induced pluripotent stem cells , 2009, Hepatology.

[121]  Rudolf Jaenisch,et al.  Parkinson's Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors , 2009, Cell.

[122]  A. Mares,et al.  HIT AND RUN , 1999 .