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Cell Therapy pp 197-226 | Cite as

Engineering Organoid Systems to Model Health and Disease

  • James A. AnkrumEmail author
  • Thomas J. Bartosh
  • Xiaolei Yin
  • Alexander J. Brown
  • Anthony J. BurandJr
  • Lauren Boland
Chapter
Part of the Molecular and Translational Medicine book series (MOLEMED)

Abstract

Much of the in vitro study of organs relies on responses from monolayers composed of one or more cell types; however, in many cases, this simplistic modeling of the organ system does not replicate how cells behave in vivo in the context of their organ and organism. While many useful cell characteristics can be deduced from 2D cell cultures, a full understanding of organ systems and biology requires studying cells in the context of their native environment. Traditionally, animal models have fulfilled this role; however, in the past decade, techniques and technologies to grow 3D tissue organoids in culture have been developed as an intermediate or replacement for in vivo studies. In this chapter, we review the genesis of organoid culture systems and provide an in-depth view of several fields that have been significantly impacted by organoid technology. Finally, we summarize emerging applications of organoids in modeling health and disease, treating patients, and discovering novel pharmaceuticals.

Keywords

Matrigel Mesenchymal stem cell Spheroid Organ on a chip Stem cells Niche Model system Drug discovery Regenerative medicine Intestinal stem cell Paracrine signaling 

References

  1. 1.
    Masters JR. TIMELINEHeLa cells 50 years on: the good, the bad and the ugly. Nat Rev Cancer. 2002;2(4):315–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Scannell JW, Bosley J. When quality beats quantity: decision theory, drug discovery, and the reproducibility crisis. PLoS One. 2016;11(2):e0147215.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Wienkers LC, Heath TG. Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov. 2005;4(10):825–33.PubMedCrossRefGoogle Scholar
  4. 4.
    Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther. 2016;7(1):125.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol. 2007;213(2):341–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell. 2012;10(6):709–16.PubMedCrossRefGoogle Scholar
  7. 7.
    Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell. 2008;2(4):313–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ankrum J, Karp JM. Mesenchymal stem cell therapy: two steps forward, one step back. Trends Mol Med. 2010;16(5):203–9.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ankrum J, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32(3):252–60.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Banfi A, Muraglia A, Dozin B, Mastrogiacomo M, Cancedda R, Quarto R. Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells. Exp Hematol. 2000;28(6):707–15.PubMedCrossRefGoogle Scholar
  11. 11.
    Kretlow JD, Jin Y-Q, Liu W, Zhang WJ, Hong T-H, Zhou G, et al. Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells. BMC Cell Biol. 2008;9(1):60.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Larson BL, Ylöstalo J, Prockop DJ. Human multipotent stromal cells undergo sharp transition from division to development in culture. Stem Cells. 2008;26(1):193–201.PubMedCrossRefGoogle Scholar
  13. 13.
    Boquest AC, Shahdadfar A, Frønsdal K, Sigurjonsson O, Tunheim SH, Collas P, et al. Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture. Mol Biol Cell. 2005;6(3):1131–41.CrossRefGoogle Scholar
  14. 14.
    Bara JJ, Richards RG, Alini M, Stoddart MJ. Concise review: bone marrow-derived mesenchymal stem cells change phenotype following in vitro culture: implications for basic research and the clinic. Stem Cells. 2014;32(7):1713–23.PubMedCrossRefGoogle Scholar
  15. 15.
    Bruder SP, Jaiswal N, Haynesworth SE. Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. J Cell Biochem. 1997;64(2):278–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Prockop DJ, Olson SD. Clinical trials with adult stem/progenitor cells for tissue repair: let’s not overlook some essential precautions. Blood. 2007;109(8):3147–51.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Moll G, Rasmusson-Duprez I, Bahr von L, Connolly-Andersen A-M, Elgue G, Funke L, et al. Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells. 2012;30(7):1565–74.PubMedCrossRefGoogle Scholar
  18. 18.
    Galipeau J. The mesenchymal stromal cells dilemma--does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy. 2013;15(1):2–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Saleh FA, Genever PG. Turning round: multipotent stromal cells, a three-dimensional revolution? Cytotherapy. 2011;13(8):903–12.PubMedCrossRefGoogle Scholar
  20. 20.
    Sart S, Tsai A-C, Li Y, Ma T. Three-dimensional aggregates of mesenchymal stem cells: cellular mechanisms, biological properties, and applications. Tissue Eng Part B Rev. 2014;20(5):365–80.PubMedCrossRefGoogle Scholar
  21. 21.
    Achilli T-M, Meyer J, Morgan JR. Advances in the formation, use and understanding of multi-cellular spheroids. Expert Opin Biol Ther. 2012;12(10):1347–60.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Spheroid culture of mesenchymal stem cells. Hindawi Publishing Corporation. http://www.hindawi.com/journals/sci/2015/837126/
  23. 23.
    Bartosh TJ, Ylostalo JH, Mohammadipoor A, Bazhanov N, Coble K, Claypool K, et al. Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc Natl Acad Sci U S A. 2010;107(31):13724–9.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Steck E, Bertram H, Abel R, Chen B, Winter A, Richter W. Induction of intervertebral disc–like cells from adult mesenchymal stem cells. Stem Cells. 2005;23(3):403–11.PubMedCrossRefGoogle Scholar
  25. 25.
    Arufe MC, la Fuente DA, Fuentes Boquete I, De Toro FJ, Blanco FJ. Differentiation of synovial CD-105+ human mesenchymal stem cells into chondrocyte-like cells through spheroid formation. J Cell Biochem. 2009;108(1):145–55.PubMedCrossRefGoogle Scholar
  26. 26.
    Potapova IA, Gaudette GR, Brink PR, Robinson RB, Rosen MR, Cohen IS, et al. Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro. Stem Cells. 2007;25(7):1761–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Frith JE, Thomson B, Genever PG. Dynamic three-dimensional culture methods enhance mesenchymal stem cell properties and increase therapeutic potential. Tissue Eng Part C Methods. 2010;16(4):735–49.PubMedCrossRefGoogle Scholar
  28. 28.
    Prockop DJ. “Stemness” does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). Clin Pharmacol Ther. 2007;82(3):241–3.PubMedCrossRefGoogle Scholar
  29. 29.
    Bahr von L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells. 2012;30(7):1575–8.CrossRefGoogle Scholar
  30. 30.
    Lee RH, Seo MJ, Pulin AA, Gregory CA, Ylostalo J, Prockop DJ. The CD34-like protein PODXL and alpha6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice. Blood. 2009;113(4):816–26.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bartosh TJ, Ylostalo JH, Bazhanov N, Kuhlman J, Prockop DJ. Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1). Stem Cells. 2013;31(11):2443–56.PubMedCrossRefGoogle Scholar
  32. 32.
    Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009;5(1):54–63.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Bazhanov N, Ylostalo JH, Bartosh TJ, Tiblow A, Mohammadipoor A, Foskett A, et al. Intraperitoneally infused human mesenchymal stem cells form aggregates with mouse immune cells and attach to peritoneal organs. Stem Cell Res Ther. 2016;7(1):27.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Ylostalo JH, Bartosh TJ, Coble K, Prockop DJ. Human mesenchymal stem/stromal cells cultured as spheroids are self-activated to produce prostaglandin E2 that directs stimulated macrophages into an anti-inflammatory phenotype. Stem Cells. 2012;30(10):2283–96.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Bartosh TJ, Ylostalo JH. Preparation of anti-inflammatory mesenchymal stem/precursor cells (MSCs) through sphere formation using hanging-drop culture technique. Curr Protoc Stem Cell Biol. 2014;28:Unit2B.6.Google Scholar
  36. 36.
    Cheng N-C, Chen S-Y, Li J-R, Young T-H. Short-term spheroid formation enhances the regenerative capacity of adipose-derived stem cells by promoting stemness, angiogenesis, and chemotaxis. Stem Cells Transl Med. 2013;2(8):584–94.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Bhang SH, Lee S, Shin J-Y, Lee T-J, Kim B-S. Transplantation of cord blood mesenchymal stem cells as spheroids enhances vascularization. Tissue Eng Part A. 2012;18(19–20):2138–47.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Ho SS, Murphy KC, Binder BYK, Vissers CB, Leach JK. Increased survival and function of mesenchymal stem cell spheroids entrapped in instructive alginate hydrogels. Stem Cells Transl Med. 2016;5(6):773–81.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Zimmermann JA, McDevitt TC. Pre-conditioning mesenchymal stromal cell spheroids for immunomodulatory paracrine factor secretion. Cytotherapy. 2014;16(3):331–45.PubMedCrossRefGoogle Scholar
  40. 40.
    Tsai A-C, Liu Y, Yuan X, Ma T. Compaction, fusion, and functional activation of three-dimensional human mesenchymal stem cell aggregate. Tissue Eng Part A. 2015;21(9–10):1705–19.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Lee EJ, Park SJ, Kang SK, Kim G-H, Kang H-J, Lee S-W, et al. Spherical bullet formation via E-cadherin promotes therapeutic potency of mesenchymal stem cells derived from human umbilical cord blood for myocardial infarction. Mol Ther. 2012;20(7):1424–33.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Murphy KC, Hoch AI, Harvestine JN, Zhou D, Leach JK. Mesenchymal stem cell spheroids retain osteogenic phenotype through α2β1 signaling. Stem Cells Transl Med. 2016;5(9):1229–37.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Cesarz Z, Funnell JL, Guan J, Tamama K. Soft elasticity-associated signaling and bone morphogenic protein 2 are key regulators of mesenchymal stem cell spheroidal aggregates. Stem Cells Dev. 2016;25(8):622–35.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Guo L, Zhou Y, Wang S, Wu Y. Epigenetic changes of mesenchymal stem cells in three-dimensional (3D) spheroids. J Cell Mol Med. 2014;18(10):2009–19.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Fennema E, Rivron N, Rouwkema J, van Blitterswijk C, de Boer J. Spheroid culture as a tool for creating 3D complex tissues. Trends Biotechnol. 2013;31(2):108–15.PubMedCrossRefGoogle Scholar
  46. 46.
    Yin X, Mead BE, Safaee H, Langer R, Karp JM, Levy O. Engineering stem cell organoids. Cell Stem Cell. 2016;18(1):25–38.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Li Y, Liu W, Liu F, Zeng Y, Zuo S, Feng S, et al. Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia. Proc Natl Acad Sci U S A. 2014;111(37):13511–6.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    O'Shaughnessy TJ, Lin HJ, Ma W. Functional synapse formation among rat cortical neurons grown on three-dimensional collagen gels. Neurosci Lett. 2003;340(3):169–72.PubMedCrossRefGoogle Scholar
  49. 49.
    Cullen DK, Stabenfeldt SE, Simon CM, Tate CC, LaPlaca MC. In vitro neural injury model for optimization of tissue-engineered constructs. J Neurosci Res. 2007;85(16):3642–51.PubMedCrossRefGoogle Scholar
  50. 50.
    Li GN, Livi LL, Gourd CM, Deweerd ES, Hoffman-Kim D. Genomic and morphological changes of neuroblastoma cells in response to three-dimensional matrices. Tissue Eng. 2007;13(5):1035–47.PubMedCrossRefGoogle Scholar
  51. 51.
    Frampton JP, Hynd MR, Shuler ML, Shain W. Fabrication and optimization of alginate hydrogel constructs for use in 3D neural cell culture. Biomed Mater. 2011;6(1):015002.PubMedCrossRefGoogle Scholar
  52. 52.
    Tang-Schomer MD, White JD, Tien LW, Schmitt LI, Valentin TM, Graziano DJ, et al. Bioengineered functional brain-like cortical tissue. Proc Natl Acad Sci U S A. 2014;111(38):13811–6.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Paşca AM, Sloan SA, Clarke LE, Tian Y, Makinson CD, Huber N, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015;12(7):671–8.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Lancaster MA, Renner M, Martin C-A, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501(7467):373–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Kraus D, Boyle V, Leibig N, Stark GB, Penna V. The neuro-spheroid—a novel 3D in vitro model for peripheral nerve regeneration. J Neurosci Methods. 2015;246:97–105.PubMedCrossRefGoogle Scholar
  56. 56.
    Dingle Y-TL, Boutin ME, Chirila AM, Livi LL, Labriola NR, Jakubek LM, et al. Three-dimensional neural spheroid culture: an in vitro model for cortical studies. Tissue Eng Part C Methods. 2015;21(12):1274–83.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S, Matsumura M, et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell. 2008;3(5):519–32.PubMedCrossRefGoogle Scholar
  58. 58.
    Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M, Sasai Y. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A. 2013;110(50):20284–9. http://www.pnas.org/cgi/doi/10.1073/pnas.1315710110 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Mariani J, Vittoria M, Palejev D, Tomasini L, Coppola G, Szekely AM, et al. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2012;109(31):12770–5.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Danjo T, Eiraku M, Muguruma K, Watanabe K, Kawada M, Yanagawa Y, et al. Subregional specification of embryonic stem cell-derived ventral telencephalic tissues by timed and combinatory treatment with extrinsic signals. J Neurosci. 2011;31(5):1919–33.PubMedCrossRefGoogle Scholar
  61. 61.
    Suga H, Kadoshima T, Minaguchi M, Ohgushi M, Soen M, Nakano T, et al. Self-formation of functional adenohypophysis in three-dimensional culture. Nature. 2011;480(7375):57–62.PubMedCrossRefGoogle Scholar
  62. 62.
    Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature. 2011;472(7341):51–6. http://www.nature.com/doifinder/10.1038/nature09941 PubMedCrossRefGoogle Scholar
  63. 63.
    Jeong GS, Chang JY, Park JS, Lee S-A, Park D, Woo J, et al. Networked neural spheroid by neuro-bundle mimicking nervous system created by topology effect. Mol Brain. 2015;8(1):17.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Lancaster MA, Knoblich JA. Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 2014;9(10):2329–40.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Nasu M, Takata N, Danjo T, Sakaguchi H, Kadoshima T, Futaki S, et al. Robust formation and maintenance of continuous stratified cortical neuroepithelium by laminin-containing matrix in mouse ES cell culture. PLoS One. 2013;7(12):e53024.CrossRefGoogle Scholar
  66. 66.
    Koch P, Opitz T, Steinbeck JA, Ladewig J, Brustle O. 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 U S A. 2009;106(9):3225–30.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Gaspard N, Bouschet T, Hourez R, Dimidschstein J, Naeije G, van den Ameele J, et al. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature. 2008;455(7211):351–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Bräuninger M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci U S A. 2015;112(51):15672–7.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Chang WWL, Leblond CP. Renewal of the epithelium in the descending colon of the mouse. I. Presence of three cell populations: vacuolated-columnar, mucous and argentaffin. Am J Anat. 1971;131(1):73–99.PubMedCrossRefGoogle Scholar
  70. 70.
    Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449(7165):1003–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Leblond CP, Inoue S. Structure, composition, and assembly of basement membrane. Am J Anat. 1989;185(4):367–90.PubMedCrossRefGoogle Scholar
  72. 72.
    Sato T, Clevers H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science. 2013;340(6137):1190–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 1998;19(4):379–83.PubMedCrossRefGoogle Scholar
  74. 74.
    Yin X, Farin HF, van Es JH, Clevers H, Langer R, Karp JM. Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny. Nat Methods. 2014;11(1):106–12.PubMedCrossRefGoogle Scholar
  75. 75.
    Dignass AU, Sturm A. Peptide growth factors in the intestine. Eur J Gastroenterol Hepatol. 2001;13(7):763–70.PubMedCrossRefGoogle Scholar
  76. 76.
    Haramis APG. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science. 2004;303(5664):1684–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Auclair BA, Benoit YD, Rivard N, Mishina Y, Perreault N. Bone morphogenetic protein signaling is essential for terminal differentiation of the intestinal secretory cell lineage. Gastroenterology. 2007;133(3):887–96.PubMedCrossRefGoogle Scholar
  78. 78.
    Batts LE, Polk DB, Dubois RN, Kulessa H. BMP signaling is required for intestinal growth and morphogenesis. Dev Dyn. 2006;235(6):1563–70.PubMedCrossRefGoogle Scholar
  79. 79.
    Crosnier C, Stamataki D, Lewis J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nat Rev Genet. 2006;7(5):349–59.PubMedCrossRefGoogle Scholar
  80. 80.
    Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 2011;469(7330):415–418. doi:10.1038/nature09637.Google Scholar
  81. 81.
    Kim KA. Mitogenic influence of human R-Spondin1 on the intestinal epithelium. Science. 2005;309(5738):1256–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Evans GS, Flint N, Somers AS, Eyden B, Potten CS. The development of a method for the preparation of rat intestinal epithelial cell primary cultures. J Cell Sci. 1992;101(Pt 1):219–31.PubMedGoogle Scholar
  83. 83.
    de Lau W, Peng WC, Gros P, Clevers H. The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 2014;28(4):305–16.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H, Toda S, et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med. 2009;15(6):701–6.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459(7244):262–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Clevers H, Loh KM, Nusse R. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 2014;346(6205):1248012.PubMedCrossRefGoogle Scholar
  87. 87.
    Pan FC, Wright C. Pancreas organogenesis: from bud to plexus to gland. Dev Dyn. 2011;240(3):530–65.PubMedCrossRefGoogle Scholar
  88. 88.
    Kopp JL, Dubois CL, Schaffer AE, Hao E, Shih HP, Seymour PA, et al. Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development. 2011;138(4):653–65.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Solar M, Cardalda C, Houbracken I, Martín M, Maestro MA, De Medts N, et al. Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev Cell. 2009;17(6):849–60.PubMedCrossRefGoogle Scholar
  90. 90.
    Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet. 2011;43(1):34–41.PubMedCrossRefGoogle Scholar
  91. 91.
    Kopinke D, Brailsford M, Shea JE, Leavitt R, Scaife CL, Murtaugh LC. Lineage tracing reveals the dynamic contribution of Hes1+ cells to the developing and adult pancreas. Development. 2011;138(3):431–41.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Inada A, Nienaber C, Katsuta H, Fujitani Y, Levine J, Morita R, et al. Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci U S A. 2008;105(50):19915–9.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010;464(7292):1149–54.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Montesano R, Mouron P, Amherdt M, Orci L. Collagen matrix promotes reorganization of pancreatic endocrine cell monolayers into islet-like organoids. J Cell Biol. 1983;97(3):935–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Jin L, Feng T, Shih HP, Zerda R, Luo A, Hsu J, et al. Colony-forming cells in the adult mouse pancreas are expandable in Matrigel and form endocrine/acinar colonies in laminin hydrogel. Proc Natl Acad Sci U S A. 2013;110(10):3907–12.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Huch M, Bonfanti P, Boj SF, Sato T, Loomans CJM, van de Wetering M, et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J. 2013;32(20):2708–21.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Lee J, Sugiyama T, Liu Y, Wang J, Gu X, Lei J, et al. Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells. elife. 2013;2:e00940.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Greggio C, De Franceschi F, Grapin-Botton A. Concise reviews: in vitro-produced pancreas organogenesis models in three dimensions: self-organization from few stem cells or progenitors. Stem Cells. 2015;33(1):8–14.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Greggio C, De Franceschi F, Figueiredo-Larsen M, Gobaa S, Ranga A, Semb H, et al. Artificial three-dimensional niches deconstruct pancreas development in vitro. Development. 2013;140(21):4452–62.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC, et al. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci U S A. 2010;107(30):13426–31.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Raikwar SP, Kim E-M, Sivitz WI, Allamargot C, Thedens DR, Zavazava N. Human iPS cell-derived insulin producing cells form vascularized organoids under the kidney capsules of diabetic mice. PLoS One. 2015;10(1):e0116582.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Chen Y-J, Finkbeiner SR, Weinblatt D, Emmett MJ, Tameire F, Yousefi M, et al. De novo formation of insulin-producing “neo-β cell islets” from intestinal crypts. Cell Rep. 2014;6(6):1046–58.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Ariyachet C, Tovaglieri A, Xiang G, Lu J, Shah MS, Richmond CA, et al. Reprogrammed stomach tissue as a renewable source of functional β cells for blood glucose regulation. Cell Stem Cell. 2016;18(3):410–21.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Fatehullah A, Tan SH, Barker N. Organoids as an in vitro model of human development and disease. Nat Cell Biol. 2016;18(3):246–54.PubMedCrossRefGoogle Scholar
  105. 105.
    Hisha H, Tanaka T, Kanno S, Tokuyama Y, Komai Y, Ohe S, et al. Establishment of a novel lingual organoid culture system: generation of organoids having mature keratinized epithelium from adult epithelial stem cells. Sci Rep. 2013;3:3224.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6(1):25–36.PubMedCrossRefGoogle Scholar
  107. 107.
    Maimets M, Rocchi C, Bron R, Pringle S, Kuipers J, Giepmans BNG, et al. Long-term in vitro expansion of salivary gland stem cells driven by Wnt signals. Stem Cell Rep. 2016;6(1):150–62.CrossRefGoogle Scholar
  108. 108.
    Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen MMA, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015;160(1–2):299–312.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Hanahan D, Weinberg R. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.PubMedCrossRefGoogle Scholar
  110. 110.
    Dekkers JF, Wiegerinck CL, de Jonge HR, Bronsveld I, Janssens HM, de Winter-de Groot KM, et al. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med. 2013;19(7):939–45.PubMedCrossRefGoogle Scholar
  111. 111.
    Nanduri LSY, Baanstra M, Faber H, Rocchi C, Zwart E, de Haan G, et al. Purification and ex vivo expansion of fully functional salivary gland stem cells. Stem Cell Rep. 2014;3(6):957–64.CrossRefGoogle Scholar
  112. 112.
    Zhang Y-G, Wu S, Xia Y, Sun J. Salmonella-infected crypt-derived intestinal organoid culture system for host-bacterial interactions. Physiol Rep. 2014;2(9):e12147.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Wilson SS, Tocchi A, Holly MK, Parks WC, Smith JG. A small intestinal organoid model of non-invasive enteric pathogen-epithelial cell interactions. Mucosal Immunol. 2015;8(2):352–61.PubMedCrossRefGoogle Scholar
  114. 114.
    Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell. 2015;162(2):375–90.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Dang J, Tiwari SK, Lichinchi G, Qin Y, Patil VS, Eroshkin AM, et al. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell. 2016;19(2):258–65.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell. 2016;18(5):591–6.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Hohwieler M, Illing A, Hermann PC, Mayer T, Stockmann M, Perkhofer L, et al. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Gut. 2016;66(3):473–86.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Baker LA, Tiriac H, Clevers H, Tuveson DA. Modeling pancreatic cancer with organoids. Trends Cancer. 2016;2(4):176–90.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Baker LA, Tiriac H, Corbo V, Boj SF, Hwang C. Abstract B16: using human patient-derived organoids to identify genetic dependencies in pancreatic cancer. Association for Cancer. 2016.Google Scholar
  120. 120.
    Boj SF, Hwang C-I, Baker LA, Chio IIC, Engle DD, Corbo V, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell. 2015;160(1–2):324–38.PubMedCrossRefGoogle Scholar
  121. 121.
    Huang L, Holtzinger A, Jagan I, BeGora M, Lohse I, Ngai N, et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat Med. 2015;21(11):1364–71.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003;22(2):151–85.PubMedCrossRefGoogle Scholar
  123. 123.
    Adams CP, Brantner VV. Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood). 2006;25(2):420–8.CrossRefGoogle Scholar
  124. 124.
    Morizane R, Lam AQ, Freedman BS, Kishi S, Valerius MT, Bonventre JV. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nat Biotechnol. 2015;33(11):1193–200.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Xinaris C, Benedetti V, Rizzo P, Abbate M, Corna D, Azzollini N, et al. In vivo maturation of functional renal organoids formed from embryonic cell suspensions. J Am Soc Nephrol. 2012;23(11):1857–68.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Bhatia SN, Ingber DE. Microfluidic organs-on-chips. Nat Biotechnol. 2014;32(8):760–72.PubMedCrossRefGoogle Scholar
  127. 127.
    Ingber DE. Reverse engineering human pathophysiology with organs-on-chips. Cell. 2016;164(6):1105–9.PubMedCrossRefGoogle Scholar
  128. 128.
    Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE. Reconstituting organ-level lung functions on a chip. Science. 2010;328(5986):1662–8.PubMedCrossRefGoogle Scholar
  129. 129.
    Jang K-J, Mehr AP, Hamilton GA, McPartlin LA, Chung S, Suh K-Y, et al. Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. Integr Biol. 2013;5(9):1119–2.CrossRefGoogle Scholar
  130. 130.
    Toh Y-C, Lim TC, Tai D, Xiao G, van Noort D, Yu H. A microfluidic 3D hepatocyte chip for drug toxicity testing. Lab Chip. 2009;9(14):2026–10.PubMedCrossRefGoogle Scholar
  131. 131.
    Esch MB, Mahler GJ, Stokol T, Shuler ML. Body-on-a-chip simulation with gastrointestinal tract and liver tissues suggests that ingested nanoparticles have the potential to cause liver injury. Lab Chip. 2014;14(16):3081–12.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Kim HJ, Li H, Collins JJ, Ingber DE. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc Natl Acad Sci U S A. 2016;113(1):E7–E15.PubMedCrossRefGoogle Scholar
  133. 133.
    Zhang YS, Arneri A, Bersini S, Shin S-R, Zhu K, Goli-Malekabadi Z, et al. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomaterials. 2016;110(c):45–59.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Viravaidya K, Shuler ML. Incorporation of 3T3-L1 cells to mimic bioaccumulation in a microscale cell culture analog device for toxicity studies. Biotechnol Prog. 2004;20(2):590–7.PubMedCrossRefGoogle Scholar
  135. 135.
    Torisawa Y-S, Spina CS, Mammoto T, Mammoto A, Weaver JC, Tat T, et al. Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro. Nat Methods. 2014;11(6):663–9.PubMedCrossRefGoogle Scholar
  136. 136.
    Jain A, Meer AD, Papa A-L, Barrile R, Lai A, Schlechter BL, et al. Assessment of whole blood thrombosis in a microfluidic device lined by fixed human endothelium. Biomed Microdevices. 2016;18(4):73.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Griep LM, Wolbers F, de Wagenaar B, Braak ter PM, Weksler BB, Romero IA, et al. BBB ON CHIP: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function. Biomed Microdevices. 2012;15(1):145–50.CrossRefGoogle Scholar
  138. 138.
    Portillo-Lara R, Annabi N. Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment. Lab Chip. 2016;16:4063–81.PubMedCrossRefGoogle Scholar
  139. 139.
    Zhou M, Ma H, Lin H, Qin J. Induction of epithelial-to-mesenchymal transition in proximal tubular epithelial cells on microfluidic devices. Biomaterials. 2014;35(5):1390–401.PubMedCrossRefGoogle Scholar
  140. 140.
    Li CY, Stevens KR, Schwartz RE, Alejandro BS, Huang JH, Bhatia SN. Micropatterned cell-cell interactions enable functional encapsulation of primary hepatocytes in hydrogel microtissues. Tissue Eng Part A. 2014;20(15–16):2200–12.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Kim HJ, Ingber DE. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation. Integr Biol. 2013;5(9):1130–40.CrossRefGoogle Scholar
  142. 142.
    Kim HJ, Huh D, Hamilton G, Ingber DE. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip. 2012;12(12):2165–74.PubMedCrossRefGoogle Scholar
  143. 143.
    Huh D, Leslie DC, Matthews BD, Fraser JP, Jurek S, Hamilton GA, et al. A human disease model of drug toxicity–induced pulmonary edema in a lung-on-a-chip microdevice. Sci Transl Med. 2012;4(159):159ra147.PubMedCrossRefGoogle Scholar
  144. 144.
    Takayama S, Ostuni E, Qian X. Topographical micropatterning of poly (dimethylsiloxane) using laminar flows of liquids in capillaries. Adv Mater. 2001;13(8):570–4.CrossRefGoogle Scholar
  145. 145.
    Folch A, Ayon A, Hurtado O, Schmidt MA, Toner M. Molding of deep polydimethylsiloxane microstructures for microfluidics and biological applications. J Biomech Eng. 1999;121(1):28–34.PubMedCrossRefGoogle Scholar
  146. 146.
    Lind JU, Busbee TA, Valentine AD, Pasqualini FS, Yuan H, Yadid M, et al. Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing. Nat Mater. 2016;16(3):303–8.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Fan J, de Lannoy IAM. Pharmacokinetics. Biochem Pharmacol. 2014;87(1):93–120.PubMedCrossRefGoogle Scholar
  148. 148.
    Esch MB, King TL, Shuler ML. The role of body-on-a-chip devices in drug and toxicity studies. Annu Rev Biomed Eng. 2011;13(1):55–72.PubMedCrossRefGoogle Scholar
  149. 149.
    Maschmeyer I, Lorenz AK, Schimek K, Hasenberg T, Ramme AP, Hübner J, et al. A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip. 2015;15:2688–99.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • James A. Ankrum
    • 1
    Email author
  • Thomas J. Bartosh
    • 2
  • Xiaolei Yin
    • 3
  • Alexander J. Brown
    • 1
  • Anthony J. BurandJr
    • 4
  • Lauren Boland
    • 5
  1. 1.Department of Biomedical Engineering, FOE Diabetes Research CenterUniversity of Iowa Hospitals and ClinicsIowa CityUSA
  2. 2.Department of Medical PhysiologyTexas A&M University Health Science CenterTempleUSA
  3. 3.Department of MedicineBrigham and Women’s HospitalBostonUSA
  4. 4.Department of Biomedical EngineeringIowa CityUSA
  5. 5.Department of Biomedical EngineeringIowa CityUSA

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