REVIEW

Genome engineering of stem cell organoids for disease modeling

  • Yingmin Sun 1,2 ,
  • Qiurong Ding , 1,2
Expand
  • 1. CAS Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
  • 2. University of Chinese Academy of Sciences, Shanghai 200031, China

Received date: 30 Nov 2016

Accepted date: 28 Dec 2016

Published date: 12 Jun 2017

Copyright

2017 The Author(s) 2017. This article is published with open access at Springerlink.com and journal.hep.com.cn

Abstract

Precision medicine emerges as a new approach that takes into account individual variability. Successful realization of precision medicine requires disease models that are able to incorporate personalized disease information and recapitulate disease development processes at the molecular, cellular and organ levels. With recent development in stem cell field, a variety of tissue organoids can be derived from patient specific pluripotent stem cells and adult stem cells. In combination with the state-of-the-art genome editing tools, organoids can be further engineered to mimic diseaserelevant genetic and epigenetic status of a patient. This has therefore enabled a rapid expansion of sophisticated in vitro disease models, offering a unique system for fundamental and biomedical research as well as the development of personalized medicine. Here we summarize some of the latest advances and future perspectives in engineering stem cell organoids for human disease modeling.

Cite this article

Yingmin Sun , Qiurong Ding . Genome engineering of stem cell organoids for disease modeling[J]. Protein & Cell, 2017 , 8(5) : 315 -327 . DOI: 10.1007/s13238-016-0368-0

1
AiharaE, MaheMM, SchumacherMA, MatthisAL, FengR, RenW, NoahTK, Matsu-uraT, MooreSR, HongCI (2015) Characterization of stem/progenitor cell cycle using murine circumvallate papilla taste bud organoid. Sci Rep5: 17185

DOI

2
AmabileA, MigliaraA, CapassoP, BiffiM, CittaroD, NaldiniL, LombardoA (2016) Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell167:219–232

DOI

3
BarkerN, HuchM, KujalaP, van de WeteringM, SnippertHJ, van EsJH, SatoT, StangeDE, BegthelH, van den BornM (2010) Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell6:25–36

DOI

4
BartfeldS, BayramT, van de WeteringM, HuchM, BegthelH, KujalaP, VriesR, PetersPJ, CleversH (2015) In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology148:126–136

DOI

5
Ben-ZviD, MeltonDA (2015) Modeling human nutrition using human embryonic stem cells. Cell161:12–17

DOI

6
BigorgneAE, FarinHF, LemoineR, MahlaouiN, LambertN, GilM, SchulzA, PhilippetP, SchlesserP, AbrahamsenTG (2014) TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J Clin Invest124:328–337

DOI

7
BojSF, HwangCI, BakerLA, ChioII, EngleDD, CorboV, JagerM, Ponz-SarviseM, TiriacH, SpectorMS (2015) Organoid models of human and mouse ductal pancreatic cancer. Cell160:324–338

DOI

8
CanverMC, SmithEC, SherF, PinelloL, SanjanaNE, ShalemO, ChenDD, SchuppPG, VinjamurDS, GarciaSP (2015) BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature527:192–197

DOI

9
ChenB, GilbertLA, CiminiBA, SchnitzbauerJ, ZhangW, LiGW, ParkJ, BlackburnEH, WeissmanJS, QiLS (2013) Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. Cell155:1479–1491

DOI

10
ChenS, SanjanaNE, ZhengK, ShalemO, LeeK, ShiX, ScottDA, SongJ, PanJQ, WeisslederR (2015) Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis. Cell160:1246–1260

DOI

11
ChengAW, WangH, YangH, ShiL, KatzY, TheunissenTW, RangarajanS, ShivalilaCS, DadonDB, JaenischR (2013) Multiplexed activation of endogenous genes by CRISPR-on, an RNA-guided transcriptional activator system. Cell Res23:1163–1171

DOI

12
ChuaCW, ShibataM, LeiM, ToivanenR, BarlowLJ, BergrenSK, BadaniKK, McKiernanJM, BensonMC, HibshooshH (2014) Single luminal epithelial progenitors can generate prostate organoids in culture. Nat Cell Biol16:951–961

DOI

13
CollinsFS, VarmusH (2015) A new initiative on precision medicine. N Engl J Med372:793–795

DOI

14
DekkersJF, WiegerinckCL, de JongeHR, BronsveldI, JanssensHM, de Winter-de GrootKM, BrandsmaAM, de JongNW, BijveldsMJ, ScholteBJ (2013) A functional CFTR assay using primary cystic fiborsis intestinal organoids. Nat Med19:939–945

DOI

15
DeWardAD, CramerJ, LagasseE (2014) Celluar heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population. Cell Rep9:701–711

DOI

16
DingQ, LeeYK, SchaeferEA, PetersDT, VeresA, KimK, KuperwasserN, MotolaDL, MeissnerTB, HendriksWT (2013) A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell12:238–251

DOI

17
DrostJ, van JaarsveldRH, PonsioenB, ZimberlinC, van BoxtelR, BuijsA, SachsN, OvermeerRM, OfferhausGJ, BegthelH (2015) Sequential cancer mutations in cultured human intestinal stem cells. Nature521:43–47

DOI

18
DyeBR, HillDR, FergusonMA, TsaiYH, NagyMS, DyalR, WellsJM, MayhewCN, NattivR, KleinOD (2015) In vitro generation of human pluripotent stem cell derived lung organoids. Elife. doi:10.7554/eLife.05098

DOI

19
EirakuM, WatanabeK, Matsuo-TakasakiM, KawadaM, YonemuraS, MatsumuraM, WatayaT, NishiyamaA, MugurumaK, SasaiY (2008) Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell3:519–532

DOI

20
EirakuM, TakataN, IshibashiH, KawadaM, SakakuraE, OkudaS, SekiguchiK, AdachiT, SasaiY (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature472:51–56

DOI

21
ForbesterJL, GouldingD, VallierL, HannanN, HaleC, PickardD, MukhopadhyayS, DouganG (2015) Interaction of Salmonella enterica Serovar Typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect Immun83:2926–2934

DOI

22
GaoD, VelaI, SbonerA, IaquintaPJ, KarthausWR, GopalanA, DowlingC, WanjalaJN, UndvallEA, AroraVK (2014) Organoid cultures derived from patients with advanced prostate cancer. Cell159:176–187

DOI

23
GaspardN, BouschetT, HourezR, DimidschsteinJ, NaeijeG, van den AmeeleJ, Espuny-CamachoI, HerpoelA, PassanteL, SchiffmannSN (2008) An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature455:351–357

DOI

24
GilbertLA, LarsonMH, MorsutL, LiuZ, BrarGA, TorresSE, Stern-GinossarN, BrandmanO, WhiteheadEH, DoudnaJA (2013) CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell154:442–451

DOI

25
GilbertLA, HorlbeckMA, AdamsonB, VillaltaJE, ChenY, WhiteheadEH, GuimaraesC, PanningB, PloeghHL, BassikMC (2014) Genome-scale CRISPR-mediated control of gene repression and activation. Cell159:647–661

DOI

26
HiltonIB, D’IppolitoAM, VockleyCM, ThakorePI, CrawfordGE, ReddyTE, GersbachCA (2015) Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol33:510–517

DOI

27
HishaH, TanakaT, KannoS, TokuyamaY, KomaiY, OheS, YanaiH, OmachiT, UenoH (2013) Establishment of a novel lingual organoid culture system: generation of organoids having mature keratinized epithelium from adult epithelial stem cells. Sci Rep3:3224

DOI

28
HsuPD, LanderES, ZhangF (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell157:1262–1278

DOI

29
HuchM, BonfantiP, BojSF, SatoT, LoomansCJ, van de WeteringM, SojoodiM, LiVS, SchuijersJ, GracaninA (2013a) Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J32:2708–2721

DOI

30
HuchM, DorrellC, BojSF, van EsJH, LiVS, van de WeteringM, SatoT, HamerK, SasakiN, FinegoldMJ (2013b) In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature494:247–250

DOI

31
HuchM, GehartH, van BoxtelR, HamerK, BlokzijlF, VerstegenMM, EllisE, van WenumM, FuchsSA, de LigtJ (2015) Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell160:299–312

DOI

32
JainIH, ZazzeronL, GoliR, AlexaK, Schatzman-BoneS, DhillonH, GoldbergerO, PengJ, ShalemO, SanjanaNE (2016) Hypoxia as a therapy for mitochondrial disease. Science 352:54–61

DOI

33
JungP, SatoT, Merlos-SuárezA, BarrigaFM, IglesiasM, RossellD, AuerH, GallardoM, BlascoMA, SanchoE (2011) Isolation and in vitro expansion of human colonic stem cells. Nat Med17:1225–1227

DOI

34
KarthausWR, IaquintaPJ, DrostJ, GracaninA, van BoxtelR, WongvipatJ, DowlingCM, GaoD, BegthelH, SachsN (2014) Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell159:163–175

DOI

35
KearnsNA, PhamH, TabakB, GengaRM, SilversteinNJ, GarberM, MaehrR (2015) Functional annotation of native enhancers with a Cas9-histone demethylase fusion. Nat Methods12:401–403

DOI

36
KoehlerKR, HashinoE (2014) 3D mouse embryonic stem cell culture for generating inner ear organoids. Nat Protoc9:1229–1244

DOI

37
KoehlerKR, MikoszAM, MoloshAI, PatelD, HashinoE (2013) Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature500:217–221

DOI

38
Koike-YusaH, LiY, TanEP, Velasco-Herrera MdelC, YusaK (2014) Genome-wide recessive genetic screening in mammalian cells with a lentiviral CRISPR-guide RNA library. Nat Biotechnol32:267–273

DOI

39
KomorAC, KimYB, PackerMS, ZurisJA, LiuDR (2016) Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature533:420–424

DOI

40
KonermannS, BrighamMD, TrevinoAE, JoungJ, AbudayyehOO, BarcenaC, HsuPD, HabibN, GootenbergJS, NishimasuH (2015) Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature517:583–588

DOI

41
KubbenN, ZhangW, WangL, VossTC, YangJ, QuJ, LiuGH, MisteliT (2016) Repression of the antioxidant NRF2 pathway in premature aging. Cell165:1361–1374

DOI

42
LancasterMA, KnoblichJA (2014) Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc9:2329–2340

DOI

43
LancasterMA, RennerM, MartinCA, WenzelD, BicknellLS, HurlesME, HomfrayT, PenningerJM, JacksonAP, KnoblichJA (2013) Cerebral organoids model human brain development and microcephaly. Nature501:373–379

DOI

44
LeeJH, BhangDH, BeedeA, HuangTL, StrippBR, BlochKD, WagersAJ, TsengYH, RyeomS, KimCF (2014) Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell156:440–455

DOI

45
LeslieJL, HuangS, OppJS, NagyMS, KobayashiM, YoungVB, SpenceJR (2015) Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect Immun83:138–145

DOI

46
LiY, ZhangW, ChangL, HanY, SunL, GongX, TangH, LiuZ, DengH, YeY (2016) Vitamin C alleviates aging defects in a stem cell model for Werner syndrome. Protein Cell7:478–488

DOI

47
LiuGH, SuzukiK, QuJ, Sancho-MartinezI, YiF, LiM, KumarS, NivetE, KimJ, SoligallaRD (2011) Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell8:688–694

DOI

48
MaH, TuLC, NaseriA, HuismanM, ZhangS, GrunwaldD, PedersonT (2016a) Multiplexed labeling of genomic loci with dCas9 and engineered sgRNAs using CRISPRainbow. Nat Biotechnol34:528–530

DOI

49
MaY, ZhangJ, YinW, ZhangZ, SongY, ChangX (2016b) Targeted AID-mediated mutagenesis(TAM) enables efficient genomic diversification in mammalian cells. Nat Methods. doi:10.1038/nmeth.4027

DOI

50
MarianiJ, SimoniniMV, PalejevD, TomasiniL, CoppolaG, SzekelyAM, HorvathTL, VaccarinoFM (2012) Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Nati Acad Sci USA109:12770–12775

DOI

51
MarianiJ, CoppolaG, ZhangP, AbyzovA, ProviniL, TomasiniL, AmenduniM, SzekelyA, PalejevD, WilsonM (2015) FOXG1-dependent dysregulation of GABA/Glutamate neuron differentiation of autism spectrum disorders. Cell162:375–390

DOI

52
MaschmeyerI, LorenzAK, SchimekK, HasenbergT, RammeAP, HübnerJ, LindnerM, DrewellC, BauerS, ThomasA (2015) A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip15:2688–2699

DOI

53
MatanoM, DateS, ShimokawaM, TakanoA, FujiiM, OhtaY, WatanabeT, KanaiT, SatoT (2015) Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat Med21:256–262

DOI

54
McCrackenKW, HowellJC, WellsJM, SpenceJR (2011) Generating human intestinal tissue from pluripotent stem cells in vitro. Nat Protoc6:1920–1928

DOI

55
McCrackenKW, CatáEM, CrawfordCM, SinagogaKL, SchumacherM, RockichBE, TsaiYH, MayhewCN, SpenceJR, ZavrosY (2014) Modeling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature516:400–404

DOI

56
MondrinosMJ, KoutzakiS, JiwanmallE, LiM, DechadarevianJP, LelkesPI, FinckCM (2006) Engineering three-dimensional pulmonary tissue constructs. Tissue Eng12:717–728

DOI

57
MondrinosMJ, JonesPL, FinckCM, LelkesPI (2014) Engineering de novo assembly of fetal pulmonary organoids. Tissue Eng Part A20:2892–2907

DOI

58
MugurumaK, NishiyamaA, OnoY, MiyawakiH, MizuharaE, HoriS, KakizukaA, ObataK, YanagawaY, HiranoT (2010) Ontogeny-recapitulating generation and tissue integration of ES cell-derived Purkinje cells. Nat Neurosci13:1171–1180

DOI

59
MugurumaK, NishiyamaA, KawakamiH, HashimotoK, SasaiY (2015) Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep10:537–550

DOI

60
MusunuruK (2013) Genome editing of human pluripotent stem cells to generate human cellular disease models. Dis Model Mech6:896–904

DOI

61
NanduriLS, BaanstraM, FaberH, RocchiC, ZwartE, de HaanG, van OsR, CoppesRP (2014) Purification and ex vivo expansion of fully functional salivary gland stem cells. Stem Cell Reports3:957–964

DOI

62
NellesDA, FangMY, O’ConnellMR, XuJL, MarkmillerSJ, DoudnaJA, YeoGW (2016) Programmable RNA tracking in live cells with CRISPR/Cas9. Cell165:488–496

DOI

63
NishidaK, ArazoeT, YachieN, BannoS, KakimotoM, TabataM, MochizukiM, MiyabeA, ArakiM, HaraKY (2016) Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems. Science. doi:10.1126/science.aaf8729

64
NoguchiTK, NinomiyaN, SekineM, KomazakiS, WangPC, AsashimaM, KurisakiA (2015) Generation of stomch tissue from mosue embryonic stem cell. Nat Cell Biol17:984–993

DOI

65
OgawaM, OgawaS, BearCE, AhmadiS, ChinS, LiB, GrompeM, KellerG, KamathBM, GhanekarA (2015) Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat Biotechnol33:853–861

DOI

66
OotaniA, LiX, SangiorgiE, HoQT, UenoH, TodaS, SugiharaH, FujimotoK, WeissmanIL, CapecchiMR (2009) Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med15:701–706

DOI

67
OzoneC, SugaH, EirakuM, KadoshimaT, YonemuraS, TakataN, OisoY, TsujiT, SasaiY (2016) Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells. Nat Commun7:10351

DOI

68
ParnasO, JovanovicM, EisenhaureTM, HerbstRH, DixitA, YeCJ, PrzybylskiD, PlattRJ, TiroshI, SanjanaNE (2015) A Genome-wide CRISPR screen in primary immune cells to dissect regulatory networks. Cell162:675–686

DOI

69
Perez-PineraP, KocakDD, VockleyCM, AdlerAF, KabadiAM, PolsteinLR, ThakorePI, GlassKA, OusteroutDG, LeongKW (2013a) RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat Methods10:973–976

DOI

70
Perez-PineraP, OusteroutDG, BrungerJM, FarinAM, GlassKA, GuilakF, CrawfordGE, HarteminkAJ, GersbachCA (2013b) Synergistic and tunable human gene activation by combinations of synthetic transcription factors. Nat Methods10:239–242

DOI

71
QiLS, LarsonMH, GilbertLA, DoudnaJA, WeissmanJS, ArkinAP, LimWA (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell152:1173–1183

DOI

72
QianX, NguyenHN, SongMM, HadionoC, OgdenSC, HammackC, YaoB, HamerskyGR, JacobF, ZhongC (2016) Brainregion-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell165:1238–1254

DOI

73
RenW, LewandowskiBC, WatsonJ, AiharaE, IwatsukiK, BachmanovAA, MargolskeeRF, JiangP (2014) Single Lgr5- or Lgr6- expressing taste stem/progenitor cells generate taste bud cells ex vivo. Proc Natl Acad Sci USA111:16401–16406

DOI

74
SampaziotisF, Cardoso de BritoM, MadrigalP, BerteroA, Saeb-ParsyK, SoaresFA, SchrumpfE, MelumE, KarlsenTH, BradleyJA (2015) Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat Biotechnol33:845–852

DOI

75
SanjanaNE, WrightJ, ZhengK, ShalemO, FontanillasP, JoungJ, ChengC, RegevA, ZhangF (2016) High-resolution interrogation of functional elements in the noncoding genome. Science353:1545–1549

DOI

76
SatoT, VriesRG, SnippertHJ, van de WeteringM, BarkerN, StangeDE, van EsJH, AboA, KujalaP, PetersPJ (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature459:262–265

DOI

77
SatoT, StangeDE, FerranteM, VriesRG, Van EsJH, Van den BrinkS, Van HoudtWJ, PronkA, Van GorpJ (2011) Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology141:1762–1772

DOI

78
SchlaermannP, ToelleB, BergerH, SchmidtSC, GlanemannM, OrdemannJ, BartfeldS, MollenkopfHJ, MeyerTF (2016) A novel human gastric primary cell culture system for modeling Helicobacter pylori infection in vitro. Gut65:201–213

DOI

79
SchmidtJC, ZaugAJ, CechTR (2016) Live cell imaging reveals the dynamics of telomerase recruitment to telomeres. Cell166:1188–1197

DOI

80
SchweigerPJ, JensenKB (2016) Modeling human disease using organotypic cultures. Curr Opin Cell Biol43:22–29

DOI

81
ShalemO, SanjanaNE, HartenianE, ShiX, ScottDA, MikkelsenTS, HecklD, EbertBL, RootDE, DoenchJG (2014) Genomescale CRISPR-Cas9 knockout screening in human cells. Science343:84–87

DOI

82
ShiJ, ZhaoY, WangK, ShiX, WangY, HuangH, ZhuangY, CaiT, WangF, ShaoF (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature526:660–665

DOI

83
SpenceJR, MayhewCN, RankinSA, KuharMF, VallanceJE, TolleK, HoskinsEE, KalinichenkoVV, WellsSI, ZornAM (2011) Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature470:105–109

DOI

84
StangeDE, KooBK, HuchM, SibbelG, BasakO, LyubimovaA, KujalaP, BartfeldS, KosterJ, GeahlenJH (2013) Differentiated Troy+ chife cells act as reserve stem cells to generate all lineages of the stomach epithelium. Cell155:357–368

DOI

85
SugaH, KadoshimaT, MinaguchiM, OhgushiM, SoenM, NakanoT, TakataN, WatayaT, MugurumaK, MiyoshiH (2011) Selfformation of functional adenohypophysis in three-dimensional culture. Nature480:57–62

DOI

86
TakahashiK, TanabeK, OhnukiM, NaritaM, IchisakaT, TomodaK, YamanakaS (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell131:861–872

DOI

87
TakasatoM, ErPX, ChiuHS, MaierB, BaillieGJ, FergusonC, PartonRG, WolvetangEJ, RoostMS, de SousaChuva, LopesSM (2015) Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature526:564–568

DOI

88
TakebeT, SekineK, EnomuraM, KoikeH, KimuraM, OgaeriT, ZhangRR, UenoY, ZhengYW, KoikeN (2013) Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature499:481–484

DOI

89
TakebeT, ZhangRR, KoikeH, KimuraM, YoshizawaE, EnomuraM, KoikeN, SekineK, TaniguchiH (2014) Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant. Nat Protoc9:396–409

DOI

90
ThakorePI, D’IppolitoAM, SongL, SafiA, ShivakumarNK, KabadiAM, ReddyTE, CrawfordGE, GersbachCA (2015) Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat Methods12:1143–1149

DOI

91
van de WeteringM, FranciesHE, FrancisJM, BounovaG, IorioF, PronkA, van HoudtW, van GorpJ, Taylor-WeinerA, KesterL (2015) Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell161:933–945

DOI

92
ViscontiRP, KasyanovV, GentileC, ZhangJ, MarkwaldRR, MironovV (2010) Towards organ printing: engineering an intra-organ branched vascular tree. Expert Opin Biol Ther10:409–420

DOI

93
WangF, QiLS (2016) Applications of CRISPR genome engineering in cell biology. Trends Cell Biol26:875–888

DOI

94
WangT, WeiJJ, SabatiniDM, LanderES (2014) Genetic screens in human cells using the CRISPR-Cas9 system. Science343:80–84

DOI

95
WangX, YamamotoY, WilsonLH, ZhangT, HowittBE, FarrowMA, KernF, NingG, HongY, KhorCC (2015) Cloning and variation of ground state intestinal stem cells. Nature522:173–178

DOI

96
WatsonCL, MaheMM, MúneraJ, HowellJC, SundaramN, PolingHM, SchweitzerJI, VallanceJE, MayhewCN, SunY (2014) An in vivo model of human small intestine using pluripotent stem cells. Nat Med20:1310–1314

DOI

97
WilsonSS, TocchiA, HollyMK, ParksWC, SmithJG (2015) A small intestinal organoid model of non-invasive enteric pathogenepithelial cell interactions. Mucosal Immunol8:352–361

DOI

98
WorkmanMJ, MaheMM, TrisnoS, PolingHM, WatsonCL, SundaramN, ChangCF, SchiesserJ, AubertP, StanleyEG (2016) Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med. doi: 10.1038/nm.4233

DOI

99
WroblewskiLE, PiazueloMB, ChaturvediR, SchumacherM, AiharaE, FengR, NotoJM, DelgadoA, IsraelDA, ZavrosY (2015) Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut64:720–730

DOI

100
YinX, FarinHF, van EsJH, CleversH, LangerR, KarpJM (2014) Niche-independent high-purify cultures of Lgr5+ intestinal stem cells and their progeny. Nat Methods11:106–112

DOI

101
YinX, MeadBE, SafaeeH, LangerR, KarpJM, LevyO (2016) Engieering stem cell organoids. Cell Stem Cell18:25–38

DOI

102
YuJ, VodyanikMA, Smuga-OttoK, Antosiewicz-BourgetJ, FraneJL, TianS, NieJ, JonsdottirGA, RuottiV, StewartR (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science318:1917–1920

DOI

103
ZhangYG, WuS, XiaY, SunJ (2014) Salmonella-infected cryptderived intestinal organoid culture system for host-bacterial interactions. Physiol Rep2(9):e12147

DOI

104
ZhangW, LiJ, SuzukiK, QuJ, WangP, ZhouJ, LiuX, RenR, XuX, OcampoA (2015) A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science348:1160–1163

DOI

105
ZhouY, ZhuS, CaiC, YuanP, LiC, HuangY, WeiW (2014) Highthroughput screening of a CRISPR/Cas9 library for functional genomics in human cells. Nature509:487–491

DOI

106
ZhuS, LiW, LiuJ, ChenCH, LiaoQ, XuP, XuH, XiaoT, CaoZ, PengJ (2016) Genome-scale deletion screening of human long non-coding RNAs using a paired-guided RNA CRISPRCas9 library. Nat Biotechnol. doi: 10.1038/nbt.3715

DOI

Outlines

/