REVIEW

Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders

  • Kimberly M. CHRISTIAN , 1,2 ,
  • Hongjun SONG 1,2,3 ,
  • Guo-li MING 1,2,3
Expand
  • 1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • 2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • 3. The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Received date: 10 Feb 2012

Accepted date: 08 Mar 2012

Published date: 01 Jun 2012

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

Cellular reprogramming allows for the de novo generation of human neurons and glial cells from patients with neurological and psychiatric disorders. Crucially, this technology preserves the genome of the donor individual and thus provides a unique opportunity for systematic investigation of genetic influences on neuronal pathophysiology. Although direct reprogramming of adult somatic cells to neurons is now possible, the majority of recent studies have used induced pluripotent stem cells (iPSCs) derived from patient fibroblasts to generate neural progenitors that can be differentiated to specific neural cell types. Investigations of monogenic diseases have established proof-of-principle for many aspects of cellular disease modeling, including targeted differentiation of neuronal populations and rescue of phenotypes in patient iPSC lines. Refinement of protocols to allow for efficient generation of iPSC lines from large patient cohorts may reveal common functional pathology and genetic interactions in diseases with a polygenic basis. We review several recent studies that illustrate the utility of iPSC-based cellular models of neurodevelopmental and neurodegenerative disorders to identify novel phenotypes and therapeutic approaches.

Cite this article

Kimberly M. CHRISTIAN , Hongjun SONG , Guo-li MING . Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders[J]. Frontiers in Biology, 2012 , 7(3) : 179 -188 . DOI: 10.1007/s11515-012-1216-0

Acknowledgments

The research in Drs. Ming and Song’s laboratories were supported by NIH, MSCRF, and March of Dimes. K.M.C was partially supported by MSCRF and Hopkins BSI.
1
Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton S A, Ding S (2011). Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell, 9(2): 113-118

DOI PMID

2
Amir R E, Van den Veyver I B, Wan M, Tran C Q, Francke U, Zoghbi H Y (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet, 23(2): 185-188

DOI PMID

3
Anderson S L, Qiu J, Rubin B Y (2003a). EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia. Biochem Biophys Res Commun, 310(2): 627-633

DOI PMID

4
Anderson S L, Qiu J, Rubin B Y (2003b). Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia. Biochem Biophys Res Commun, 306(1): 303-309

DOI PMID

5
Bock C, Kiskinis E, Verstappen G, Gu H, Boulting G, Smith Z D, Ziller M, Croft G F, Amoroso M W, Oakley D H, Gnirke A, Eggan K, Meissner A (2011). Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell, 144(3): 439-452

DOI PMID

6
Boulting G L, Kiskinis E, Croft G F, Amoroso M W, Oakley D H, Wainger B J, Williams D J, Kahler D J, Yamaki M, Davidow L, Rodolfa C T, Dimos J T, Mikkilineni S, MacDermott A B, Woolf C J, Henderson C E, Wichterle H, Eggan K (2011). A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol, 29(3): 279-286

DOI PMID

7
Brennand K J, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, Gage F H (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature, 473(7346): 221-225

DOI PMID

8
Caiazzo M, Dell’Anno M T, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova T D, Menegon A, Roncaglia P, Colciago G, Russo G, Carninci P, Pezzoli G, Gainetdinov R R, Gustincich S, Dityatev A, Broccoli V (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature, 476(7359): 224-227

DOI PMID

9
Chambers S M, Studer L (2011). Cell fate plug and play: direct reprogramming and induced pluripotency. Cell, 145(6): 827-830

DOI PMID

10
Cheung A Y, Horvath L M, Grafodatskaya D, Pasceri P, Weksberg R, Hotta A, Carrel L, Ellis J (2011). Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum Mol Genet, 20(11): 2103-2115

DOI PMID

11
Chiang C H, Su Y, Wen Z, Yoritomo N, Ross C A, Margolis R L, Song H, Ming G L (2011). Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Mol Psychiatry, 16(4): 358-360

DOI PMID

12
Duan X, Chang J H, Ge S, Faulkner R L, Kim J Y, Kitabatake Y, Liu X B, Yang C H, Jordan J D, Ma D K, Liu C Y, Ganesan S, Cheng H J, Ming G L, Lu B, Song H (2007). Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell, 130(6): 1146-1158

DOI PMID

13
Falk A, Koch P, Kesavan J, Takashima Y, Ladewig J, Alexander M, Wiskow O, Tailor J, Trotter M, Pollard S, Smith A, Brüstle O (2012). Capture of neuroepithelial-like stem cells from pluripotent stem cells provides a versatile system for in vitro production of human neurons. PLoS ONE, 7(1): e29597

DOI PMID

14
Faulkner R L, Jang M H, Liu X B, Duan X, Sailor K A, Kim J Y, Ge S, Jones E G, Ming G L, Song H, Cheng H J (2008). Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc Natl Acad Sci USA, 105(37): 14157-14162

DOI PMID

15
Gore A, Li Z, Fung H L, Young J E, Agarwal S, Antosiewicz-Bourget J, Canto I, Giorgetti A, Israel M A, Kiskinis E, Lee J H, Loh Y H, Manos P D, Montserrat N, Panopoulos A D, Ruiz S, Wilbert M L, Yu J, Kirkness E F, Izpisua Belmonte J C, Rossi D J, Thomson J A, Eggan K, Daley G Q, Goldstein L S, Zhang K (2011). Somatic coding mutations in human induced pluripotent stem cells. Nature, 471(7336): 63-67

DOI PMID

16
Hansen D V, Rubenstein J L, Kriegstein A R (2011). Deriving excitatory neurons of the neocortex from pluripotent stem cells. Neuron, 70(4): 645-660

DOI PMID

17
Harrison P J, Weinberger D R (2005). Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry, 10:40-68

18
Herbert M R (2010). Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol, 23(2): 103-110

19
Hussein S M, Batada N N, Vuoristo S, Ching R W, Autio R, Närvä E, Ng S, Sourour M, Hämäläinen R, Olsson C, Lundin K, Mikkola M, Trokovic R, Peitz M, Brüstle O, Bazett-Jones D P, Alitalo K, Lahesmaa R, Nagy A, Otonkoski T (2011). Copy number variation and selection during reprogramming to pluripotency. Nature, 471(7336): 58-62

DOI PMID

20
Israel M A, Yuan S H, Bardy C, Reyna S M, Mu Y, Herrera C, Hefferan M P, Van Gorp S, Nazor K L, Boscolo F S, Carson C T, Laurent L C, Marsala M, Gage F H, Remes A M, Koo E H, Goldstein L S (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature, 482(7384): 216-220

PMID

21
Jiang H, Ren Y, Yuen E Y, Zhong P, Ghaedi M, Hu Z, Azabdaftari G, Nakaso K, Yan Z, Feng J (2012). Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun, 3: 668

DOI PMID

22
Juopperi T A, Song H, Ming G L (2011). Modeling neurological diseases using patient-derived induced pluripotent stem cells. Future Neurol, 6(3): 363-373

DOI PMID

23
Keller F, Persico A M (2003). The neurobiological context of autism. Mol Neurobiol 28(1): 1-22

24
Kim J Y, Duan X, Liu C Y, Jang M H, Guo J U, Pow-anpongkul N, Kang E, Song H, Ming G L (2009). DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron, 63(6): 761-773

DOI PMID

25
Kim K Y, Hysolli E, Park I H (2011). Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome. Proc Natl Acad Sci USA, 108(34): 14169-14174

DOI PMID

26
Koch P, Opitz T, Steinbeck J A, Ladewig J, Brüstle O (2009). A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proc Natl Acad Sci USA, 106(9): 3225-3230

DOI PMID

27
Krencik R, Weick J P, Liu Y, Zhang Z J, Zhang S C (2011). Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol, 29(6): 528-534

DOI PMID

28
Lee G, Papapetrou E P, Kim H, Chambers S M, Tomishima M J, Fasano C A, Ganat Y M, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L (2009). Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature, 461(7262): 402-406

DOI PMID

29
Lister R, Pelizzola M, Kida Y S, Hawkins R D, Nery J R, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson J A, Evans R M, Ecker J R (2011). Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature, 471(7336): 68-73

DOI PMID

30
Mao Y, Ge X, Frank C L, Madison J M, Koehler A N, Doud M K, Tassa C, Berry E M, Soda T, Singh K K, Biechele T, Petryshen T L, Moon R T, Haggarty S J, Tsai L H (2009). Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell, 136(6): 1017-1031

DOI PMID

31
Martin I, Dawson V L, Dawson T M (2011). Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet, 12(1): 301-325

DOI PMID

32
Marchetto M C, Carromeu C, Acab A, Yu D, Yeo G W, Mu Y, Chen G, Gage F H, Muotri A R (2010). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell, 143(4): 527-39

33
Millar J K, Wilson-Annan J C, Anderson S, Christie S, Taylor M S, Semple C A, Devon R S, St Clair D M, Muir W J, Blackwood D H, Porteous D J (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet, 9(9): 1415-1423

DOI PMID

34
Nguyen H N, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, Kee K, Schüle B, Dolmetsch R E, Langston W, Palmer T D, Pera R R (2011). LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell, 8(3): 267-280

DOI PMID

35
Pang Z P, Yang N, Vierbuchen T, Ostermeier A, Fuentes D R, Yang T Q, Citri A, Sebastiano V, Marro S, Südhof T C, Wernig M (2011). Induction of human neuronal cells by defined transcription factors. Nature, 476(7359): 220-223

PMID

36
Park I H, Zhao R, West J A, Yabuuchi A, Huo H, Ince T A, Lerou P H, Lensch M W, Daley G Q (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature, 451(7175): 141-146

DOI PMID

37
Paşca S P, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Paşca A M, Cord B, Palmer T D, Chikahisa S, Nishino S, Bernstein J A, Hallmayer J, Geschwind D H, Dolmetsch R E (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med, 17(12): 1657-1662

DOI PMID

38
Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Björklund A, Lindvall O, Jakobsson J, Parmar M (2011). Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci USA, 108(25): 10343-10348

DOI PMID

39
Pomp O, Dreesen O, Leong D F, Meller-Pomp O, Tan T T, Zhou F, Colman A (2011). Unexpected X chromosome skewing during culture and reprogramming of human somatic cells can be alleviated by exogenous telomerase. Cell Stem Cell, 9(2): 156-165

DOI PMID

40
Qiang L, Fujita R, Yamashita T, Angulo S, Rhinn H, Rhee D, Doege C, Chau L, Aubry L, Vanti W B, Moreno H, Abeliovich A (2011). Directed conversion of Alzheimer’s disease patient skin fibroblasts into functional neurons. Cell, 146(3): 359-371

DOI PMID

41
Ross C A, Margolis R L, Reading S A, Pletnikov M, Coyle J T (2006). Neurobiology of schizophrenia. Neuron, 52(1): 139-153

DOI PMID

42
Sachs N A, Sawa A, Holmes S E, Ross C A, DeLisi L E, Margolis R L (2005). A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry, 10(8): 758-764

DOI PMID

43
Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D (2011). Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J Neurosci, 31(16): 5970-5976

DOI PMID

44
Shi Y, Kirwan P, Smith J, Robinson H P, Livesey F J (2012). Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat Neurosci, 15(3): 477-486

DOI PMID

45
Slaugenhaupt S A, Blumenfeld A, Gill S P, Leyne M, Mull J, Cuajungco M P, Liebert C B, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod F B, Gusella J F (2001). Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet, 68(3): 598-605

DOI PMID

46
Slaugenhaupt S A, Mull J, Leyne M, Cuajungco M P, Gill S P, Hims M M, Quintero F, Axelrod F B, Gusella J F (2003). Rescue of a human mRNA splicing defect by the plant cytokinin kinetin. Hum Mol Genet, 13(4): 429-436

DOI PMID

47
Soldner F, Laganière J, Cheng A W, Hockemeyer D, Gao Q, Alagappan R, Khurana V, Golbe L I, Myers R H, Lindquist S, Zhang L, Guschin D, Fong L K, Vu B J, Meng X, Urnov F D, Rebar E J, Gregory P D, Zhang H S, Jaenisch R (2011). Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell, 146(2): 318-331

DOI PMID

48
Spitzer N C (2006). Electrical activity in early neuronal development. Nature, 444(7120): 707-712

DOI PMID

49
St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, Gosden C, Evans H J (1990). Association within a family of a balanced autosomal translocation with major mental illness. Lancet, 336(8706): 13-16

DOI PMID

50
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5): 861-872

DOI PMID

51
Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4): 663-676

DOI PMID

52
Tchieu J, Kuoy E, Chin M H, Trinh H, Patterson M, Sherman S P, Aimiuwu O, Lindgren A, Hakimian S, Zack J A, Clark A T, Pyle A D, Lowry W E, Plath K (2010). Female human iPSCs retain an inactive X chromosome. Cell Stem Cell, 7(3): 329-342

DOI PMID

53
Tropea D, Giacometti E, Wilson N R, Beard C, McCurry C, Fu D D, Flannery R, Jaenisch R, Sur M (2009). Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA, 106(6): 2029-2034

DOI PMID

54
Uhlhaas P J, Singer W (2010). Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci, 11(2): 100-113

DOI PMID

55
Vierbuchen T, Ostermeier A, Pang Z P, Kokubu Y, Südhof T C, Wernig M (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 463(7284): 1035-1041

DOI PMID

56
Weinberger D R (1987). Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry, 44(7): 660-669

DOI PMID

57
Yoo A S, Sun A X, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch R E, Tsien R W, Crabtree G R (2011). MicroRNA-mediated conversion of human fibroblasts to neurons. Nature, 476(7359): 228-231

DOI PMID

58
Yu J, Vodyanik M A, SmugaOtto K, Antosiewicz-Bourget J, Frane J L, Tian S, Nie J, Jonsdottir G A, Ruotti V, Stewart R, Slukvin I I, Thomson J A (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858): 1917-1920

DOI PMID

Outlines

/