Tolga SEVER, Ilgın ÇEVİK, Ender Berat ELLİDOKUZ, Gizem ÇALIBAŞI KOCAL, Yasemin BAŞBİNAR

ORGANOID AS A NOVEL TECHNOLOGY FOR DISEASE MODELING

The organoid technology is capable to create more real-like in vitro models in terms of structure andfunction of the origin of the tissue. Since the three-dimensional model is able to illustrate diseasepathology, cell differentiation, and recapitulation of self-renewal, lead organoid technology as a promisingdisease model to fill the gap between conventional two-dimensional, and in vivo disease models. Thereview describes the recent development of organoid disease modeling approaches.

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1. Duval K, Grover H, Han LH, et al. Modeling physiological events in 2d vs. 3d cell culture. Physiology (bethesda) 2017; 32(4):266-277.
2. Byrne AT, Alférez DG, Amant F, et al. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat Rev Cancer 2017; 17(4):254-268.
3. Haycock JW. 3D cell culture: a review of current approaches and techniques. Methods Mol Biol 2011; 695:1-15.
4. Mahe MM, Aihara E, Schumacher MA, et al. Establishment of gastrointestinal epithelial organoids. Curr Protoc Mouse Biol 2013; 3(4):217- 240.
5. Takebe T, Zhang RR, Koike H, et al. Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant. Nat Protoc 2014; 9(2):396-409.
6. Schreurs RRCE, Baumdick ME, Sagebiel AF, et al. Human fetal tnf-α-cytokine-producing cd4+ effector memory T cells promote intestinal development and mediate inflammation early in life. Immunity 2019; 50(2):462-476.
7. Noel G, Baetz NW, Staab JF, et al. A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and hostpathogen interactions. Sci Rep 2017; 7:45270.
8. Koike H, Iwasawa K, Ouchi R, et al. Modelling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary. Nature 2019; 574(7776):112-116.
9. Fujii M, Matano M, Nanki K, Sato T. Efficient genetic engineering of human intestinal organoids using electroporation. Nat Protoc 2015; 10(10):1474-1485.
10. Dutta D, Heo I, Clevers H. Disease modeling in stem cell-derived 3d organoid systems. Trends Mol Med 2017; 23(5):393-410.
11. Liu B, Song Y, Liu D. Recent development in clinical applications of PD-1 and PD-L1 antibodies for cancer immunotherapy. J Hematol Oncol 2017; 10(174).
12. Pang Y, Hou X, Yang C, Liu Y, Jiang G. Advances on chimeric antigen receptor-modified t-cell therapy for oncotherapy. Mol Cancer 2018; 17(1):91.
13. Zhou J, Su J, Fu X, Zheng L, Yin Z. Microfluidic device for primary tumor spheroid isolation. Exp Hematol Oncol 2017; 6:22.
14. Ben-David U, Ha G, Tseng YY, et al. Patientderived xenografts undergo mouse-specific tumor evolution. Nat Genet 2017; 49(11):1567- 1575.
15. Na JC, Kim JH, Kim SY, et al. Establishment of patient-derived three-dimensional organoid culture in renal cell carcinoma. Investig Clin Urol 2020; 61(2):216-223.
16. van de Wetering M, Francies HE, Francis JM, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 2015; 161(4):933-945.
17. Weeber F, van de Wetering M, Hoogstraat M, et al. Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases. Proc Natl Acad Sci U S A 2015; 112(43):13308-13311.
18. Gao D, Vela I, Sboner A, et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 2014; 159(1):176-187.
19. Hill SJ, Decker B, Roberts EA, et al. Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids. Cancer Discov 2018; 8(11):1404-1421.
20. Fujii M, Shimokawa M, Date S, et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 2016; 18(6):827- 838.
21. Yeung TM, Gandhi SC, Wilding JL, Muschel R, Bodmer WF. Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci U S A 2010; 107(8):3722-3727.
22. Onuma K, Ochiai M, Orihashi K, et al. Genetic reconstitution of tumorigenesis in primary intestinal cells. Proc Natl Acad Sci U S A 2013; 110(27):11127-11132.
23. Matano M, Date S, Shimokawa M, et al. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat Med 2015; 21(3):256-262.
24. Scanu T, Spaapen RM, Bakker JM, et al. Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma. Cell Host Microbe 2015; 17(6):763-774.
25. Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 2017; 23(4):517-525.
26. Driehuis E, Kretzschmar K, Clevers H. Establishment of patient-derived cancer organoids for drug-screening applications. Nat Protoc 2021; 15(10):3380-3409.
27. Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 2018; 359(6378):920-926.
28. Ganesh K, Wu C, O'Rourke KP, et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nat Med 2019; 25(10):1607-1614.
29. Yoshida GJ. Applications of patient-derived tumor xenograft models and tumor organoids. J Hematol Oncol 2020; 13(1):4.
30. Benson CA, Powell HR, Liput M, et al. Immune factor, TNFα, disrupts human brain organoid development similar to schizophreniaschizophrenia ıncreases developmental vulnerability to TNFα. Front Cell Neurosci 2020; 14:233.
31. Daviaud N, Chevalier C, Friedel RH, Zou H. Distinct vulnerability and resilience of human neuroprogenitor subtypes in cerebral organoid model of prenatal hypoxic ınjury. Front Cell Neurosci 2019; 13:336.
32. Simmnacher K, Lanfer J, Rizo T, Kaindl J, Winner B. Modeling cell-cell ınteractions in parkinson's disease using human stem cell-based models. front cell neurosci 2020; 13:571.
33. Chen A, Guo Z, Fang L, Bian S. Application of fused organoid models to study human brain development and neural disorders. Front Cell Neurosci 2020; 14:133.
34. Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013; 339(6121):819-823.
35. Zou X, Owusu M, Harris R, Jackson SP, Loizou JI, Nik-Zainal S. Validating the concept of mutational signatures with isogenic cell models. Nat Commun 2018; 9(1):1744.
36. Perez-Lanzon M, Kroemer G, Maiuri MC. Organoids for modeling genetic diseases. Int Rev Cell Mol Biol 2018; 337:49-81.
37. De Boeck K, Vermeulen F, Dupont L. The diagnosis of cystic fibrosis. Presse Med 2017; 46(6 Pt 2):e97-e108.
38. Schwank G, Koo BK, Sasselli V, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 2013; 13(6):653-658.
39. Artegiani B, Clevers H. Use and application of 3Dorganoid technology. Hum Mol Genet 2018; 27(2):99-107.
40. Jo J, Xiao Y, Sun AX, et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 2016; 19(2):248-257.
41. Paşca AM, Sloan SA, Clarke LE, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods 2015; 12(7):671-678.
42. Hossein F. An overview of the current medical literature on Zika virus. Biophys Rev 2020; 12(5):1133-1138.
43. Qian X, Nguyen HN, Jacob F, Song H, Ming GL. Using brain organoids to understand Zika virusinduced microcephaly. Development 2017; 144(6):952-957.
44. Xu M, Lee EM, Wen Z, et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med 2016; 22(10):1101- 1107.
45. Zhou T, Tan L, Cederquist GY, et al. High-content screening in hPSC-neural progenitors identifies drug candidates that inhibit Zika virus infection in fetal-like organoids and adult brain. Cell Stem Cell 2017; 21(2):274-283.
46. Moriguchi T, Harii N, Goto J, et al. A first case of meningitis/encephalitis associated with SARSCoronavirus-2. Int J Infect Dis 2020; 94:55-58.
47. Montalvan V, Lee J, Bueso T, De Toledo J, Rivas K. Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review. Clin Neurol Neurosurg 2020; 194:105921.
48. Pellegrini L, Albecka A, Mallery DL, Kellner MJ, Paul D, Carter AP, et al. SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-csf barrier in human brain organoids. Cell Stem Cell 2020; 27(6): 951–961.
49. Mullenders J, de Jongh E, Brousali A, et al. Mouse and human urothelial cancer organoids: A tool for bladder cancer research. Proc Natl Acad Sci USA 2019; 116(10):4567-4574.
50. Yao Y, Xu X, Yang L, et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell 2020; 26(1):17-26.
51. Schnalzger TE, de Groot MH, Zhang C, et al. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. EMBO J 2019; 38(12):e100928.
52. Drost J, van Jaarsveld RH, Ponsioen B, et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature 2015; 521(7550):43- 47.
53. Yang L, Liu B, Chen H, et al. Progress in the application of organoids to breast cancer research. J Cell Mol Med 2020; 24(10):5420- 5427.
54. Griscelli F, Oudrhiri N, Feraud O, et al. Generation of induced pluripotent stem cell (iPSC) line from a patient with triple negative breast cancer with hereditary exon 17 deletion of BRCA1 gene. Stem Cell Res 2017; 24:135-138.
55. Sachs N, de Ligt J, Kopper O, et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 2018; 172(1-2):373- 386.
56. Hwang JW, Desterke C, Féraud O, et al. IPSCderived cancer organoids recapitulate genomic and phenotypic alterations of c-met-mutated hereditary kidney cancer. BioRxiv 2019. DOI: 10.1101/518456
57. Wang S, Gao D, Chen Y. The potential of organoids in urological cancer research. Nat Rev Urol 2017; 14(7):401-414.
58. Batchelder CA, Martinez ML, Duru N, Meyers FJ, Tarantal AF. Three dimensional culture of human renal cell carcinoma organoids. PLoS One 2015; 10(8):e0136758.
59. Nanki Y, Chiyoda T, Hirasawa A, et al. Patientderived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing. Sci Rep 2020; 10(1):12581.
60. Kopper O, de Witte CJ, Lõhmussaar K, et al. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nat Med 2019; 25(5):838-849.
61. Shi R, Radulovich N, Ng C, et al. Organoid cultures as preclinical models of non-small cell lung cancer. Clin Cancer Res 2020; 26(5):1162- 1174.
62. Kim M, Mun H, Sung CO, et al. Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat Commun 2019; 10(1):3991.
63. Dijkstra KK, Cattaneo CM, Weeber F, et al. Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 2018; 174(6):1586-1598.
64. Broutier L, Mastrogiovanni G, Verstegen MM, et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat Med 2017; 23(12):1424-1435.
65. Bhaduri A, Andrews MG, Mancia Leon W, et al. Cell stress in cortical organoids impairs molecular subtype specification. Nature 2020; 578(7793):142-148.
66. Ballabio C, Anderle M, Gianesello M, et al. Modeling medulloblastoma in vivo and with human cerebellar organoids. Nat Commun 2020; 11(1):583.
67. Jacob F, Salinas RD, Zhang DY, et al. A patientderived glioblastoma organoid model and biobank recapitulates inter- and intra-tumoral heterogeneity. Cell 2020; 180(1):188-204.
68. Beshiri ML, Tice CM, Tran C, et al. A PDX/organoid biobank of advanced prostate cancers captures genomic and phenotypic heterogeneity for disease modeling and therapeutic screening. Clin Cancer Res 2018; 24(17):4332-4345.
69. Dunnack JJ, LoTurco JJ. Of Mice and Men: Species-specific organoid models of neocortical malformation. Cell Stem Cell 2017; 20(4):421- 422.
70. Gabriel E, Ramani A, Altinisik N, Gopalakrishnan J. Human brain organoids to decode mechanisms of microcephaly. Front Cell Neurosci 2020; 14:115.
71. Kelava I, Lancaster MA. Stem cell models of human brain development. Cell Stem Cell 2016; 18(6):736-748.
72. Chan WK, Griffiths R, Price DJ, Mason JO. Cerebral organoids as tools to identify the developmental roots of autism. Mol Autism 2020; 11(1):58.
73. Hohmann SS, Ilieva M, Michel TM. In vitro models for ASD-patient-derived iPSCs and cerebral organoids. Prog Mol Biol Transl Sci 2020; 173:355-375.
74. Mariani J, Coppola G, Zhang P, et al. FOXG1- dependent dysregulation of gaba/glutamate neuron differentiation in autism spectrum disorders. Cell 2015; 162(2):375-390.
75. Papaspyropoulos A, Tsolaki M, Foroglou N, Pantazaki AA. Modeling and targeting alzheimer's disease with organoids. Front Pharmacol 2020; 11:396.
76. Kim SJ, Li J, Mahairaki V. Stem cell-derived threedimensional (organoid) models of Alzheimer's disease: a precision medicine approach. Neural Regen Res 2021; 16(8):1546-1547.
77. Monzel AS, Smits LM, Hemmer K, et al. Derivation of human midbrain-specific organoids from neuroepithelial stem cells. stem cell reports 2017; 8(5):1144-1154.
78. Sommer CA, Capilla A, Molina-Estevez FJ, et al. Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells. PLoS One 2018; 13(7):e0200657.
79. Crespo M, Vilar E, Tsai SY, et al. Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing [published correction appears in Nat Med. 2018 Apr 10;24(4):526]. Nat Med 2017; 23(7):878-884.
80. Berkers G, van Mourik P, Vonk AM, et al. Rectal organoids enable personalized treatment of cystic fibrosis. Cell Rep 2019; 26(7):1701-1708.
81. Dekkers JF, Wiegerinck CL, de Jonge HR, et al. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med 2013; 19(7):939-945.
82. Guan Y, Xu D, Garfin PM, et al. Human hepatic organoids for the analysis of human genetic diseases. JCI Insight 2017; 2(17):e94954.
83. Freedman BS, Brooks CR, Lam AQ, et al. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 2015; 6:8715.
84. Bershteyn M, Nowakowski TJ, Pollen AA, et al. Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial glia. Cell Stem Cell 2017; 20(4):435-449.
85. Iefremova V, Manikakis G, Krefft O, et al. An Organoid-based model of cortical development identifies non-cell-autonomous defects in wnt signaling contributing to miller-dieker syndrome. Cell Rep 2017; 19(1):50-59.
86. Gomes AR, Fernandes TG, Vaz SH, et al. Modeling rett syndrome with human patientspecific forebrain organoids. Front Cell Dev Biol 2020; 8:610427.
87. Feldman D, Banerjee A, Sur M. Developmental dynamics of rett syndrome. Neural Plast 2016; 2016:6154080.
88. Sloan SA, Andersen J, Pașca AM, Birey F, Pașca SP. Generation and assembly of human brain region-specific three-dimensional cultures. Nat Protoc 2018; 13(9):2062-2085.
89. Bigorgne AE, Farin HF, Lemoine R, et al. TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J Clin Invest 2014; 124(1):328-337.
90. Watanabe M, Buth JE, Vishlaghi N, et al. Selforganized cerebral organoids with humanspecific features predict effective drugs to combat Zika virus infection. Cell Rep 2017; 21(2):517- 532.
91. Lamers MM, Beumer J, van der Vaart J, et al. SARS-CoV-2 productively infects human gut enterocytes. Science 2020; 369(6499):50-54.
92. Bartfeld S, Clevers H. Organoids as model for ınfectious diseases: culture of human and murine stomach organoids and microinjection of Helicobacter Pylori. J Vis Exp 2015; (105):53359.