Skip to main content
SpringerLink
Log in

Toward Organs on Demand: Breakthroughs and Challenges in Models of Organogenesis

  • Tissue Engineering and Regenerative Medicine: Organogenesis (Bryan Brown and Christopher L. Dearth,Section Editors)
  • Published:
Current Pathobiology Reports

Abstract

Purpose of Review

Irreversible organ failure remains a worldwide concern as demand for transplantable organs far outpaces the available supply. Apart from the demand for replacement organs to use to treat irreversible organ failure in civilian, there is a need of tissues or organs for wounded soldiers returning from battle. This review will discuss traditional three-dimensional (3D) cell culture techniques as well as newly developed technology platforms for the generation of transplantable tissues and organs on demand.

Recent Findings

Since their discovery, stem cells have held great promise for their application in tissue regenerative medicine. Considerable effort is presently being invested in establishing methods for engineering physiologically relevant organs, where the chemical, physical and mechanical microenvironment of the stem cell niche can be replicated.

Summary

The recently established methods provide new possibilities in the creation of human body parts and provide more accurate predictions of tissue response to drug and chemical challenges. Given the rapid advancement in the human-induced pluripotent stem cell (iPSC) field, these platforms also hold great promise in the engineering of transplantable tissues and organs, capable of benefitting patients with end-stage chronic organ failure or wounded warrior.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance

  1. Reemtsma K, McCracken BH, Schlegel JU, Pearl MA, Pearce CW, Dewitt CW et al (1964) Renal heterotransplantation in man. Ann Surg 160:384–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Li S, Waer M, Billiau AD (2009) Xenotransplantation: role of natural immunity. Transpl Immunol 21(2):70–74

    Article  PubMed  Google Scholar 

  3. Scalea J, Hanecamp I, Robson SC, Yamada K (2012) T-cell-mediated immunological barriers to xenotransplantation. Xenotransplantation 19(1):23–30

    Article  PubMed  PubMed Central  Google Scholar 

  4. Griesemer AD, Sorenson EC, Hardy MA (2010) The role of the thymus in tolerance. Transplantation 90(5):465–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Abe M, Qi J, Sykes M, Yang YG (2002) Mixed chimerism induces donor-specific T-cell tolerance across a highly disparate xenogeneic barrier. Blood 99(10):3823–3829

    Article  CAS  PubMed  Google Scholar 

  6. Griesemer A, Yamada K, Sykes M (2014) Xenotransplantation: immunological hurdles and progress toward tolerance. Immunol Rev 258(1):241–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Boneva RS, Folks TM, Chapman LE (2001) Infectious disease issues in xenotransplantation. Clin Microbiol Rev 14(1):1–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Christopherson GT, Nesti LJ (2011) Stem cell applications in military medicine. Stem Cell Res Therapy. 2(5):40

    Article  Google Scholar 

  9. Little MT, Storb R (2002) History of haematopoietic stem-cell transplantation. Nat Rev Cancer 2(3):231–238

    Article  CAS  PubMed  Google Scholar 

  10. Freshney RI, Freshney RI (2005) Organotypic culture. Wiley, Cult Anim Cells

    Book  Google Scholar 

  11. Fell HB, Robison R (1929) The growth, development and phosphatase activity of embryonic avian femora and limb-buds cultivated in vitro. Biochem J 23(4):767–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen JM (1954) The cultivation in fluid medium of organised liver, pancreas and other tissues of foetal rats. Exp Cell Res 7(2):518–529

    Article  CAS  PubMed  Google Scholar 

  13. Ferrari D, Binda E, De Filippis L, Vescovi AL. Isolation of neural stem cells from neural tissues using the neurosphere technique. Current protocols in stem cell biology. 2010;Chapter 2:Unit2D 6

  14. Su G, Zhao Y, Wei J, Han J, Chen L, Xiao Z et al (2013) The effect of forced growth of cells into 3D spheres using low attachment surfaces on the acquisition of stemness properties. Biomaterials 34(13):3215–3222

    Article  CAS  PubMed  Google Scholar 

  15. Pastrana E, Silva-Vargas V, Doetsch F (2011) Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8(5):486–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Suslov ON, Kukekov VG, Ignatova TN, Steindler DA (2002) Neural stem cell heterogeneity demonstrated by molecular phenotyping of clonal neurospheres. Proc Natl Acad Sci USA 99(22):14506–14511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Seeds NW (1971) Biochemical differentiation in reaggregating brain cell culture. Proc Natl Acad Sci USA 68(8):1858–1861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zanoni M, Piccinini F, Arienti C, Zamagni A, Santi S, Polico R et al (2016) 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. Sci Reports. 6:19103

    Article  CAS  Google Scholar 

  19. Ware MJ, Colbert K, Keshishian V, Ho J, Corr SJ, Curley SA, et al. Generation of Homogenous Three-Dimensional Pancreatic Cancer Cell Spheroids Using an Improved Hanging Drop Technique. Tissue engineering Part C, Methods. 2016

  20. Haisler WL, Timm DM, Gage JA, Tseng H, Killian TC, Souza GR (2013) Three-dimensional cell culturing by magnetic levitation. Nat Protoc 8(10):1940–1949

    Article  CAS  PubMed  Google Scholar 

  21. Lancaster MA, Knoblich JA (2014) Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345(6194):1247125

    Article  PubMed  Google Scholar 

  22. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML et al (2006) Generation of a functional mammary gland from a single stem cell. Nature 439(7072):84–88

    Article  CAS  PubMed  Google Scholar 

  23. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE et al (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459(7244):262–265

    Article  CAS  PubMed  Google Scholar 

  24. Rookmaaker MB, Schutgens F, Verhaar MC, Clevers H (2015) Development and application of human adult stem or progenitor cell organoids. Nature Reviews Nephrol. 11(9):546–554

    Article  CAS  Google Scholar 

  25. Cramer JM, Thompson T, Geskin A, LaFramboise W, Lagasse E (2015) Distinct human stem cell populations in small and large intestine. PLoS One 10(3):e0118792

    Article  PubMed  PubMed Central  Google Scholar 

  26. DeWard AD, Cramer J, Lagasse E (2014) Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population. Cell Rep. 9(2):701–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huch M, Koo B-K (2015) Modeling mouse and human development using organoid cultures. Development. 142(18):3113–3125

    Article  CAS  PubMed  Google Scholar 

  28. Nantasanti S, Spee B, Kruitwagen HS, Chen C, Geijsen N, Oosterhoff LA et al (2015) Disease modeling and gene therapy of copper storage disease in canine hepatic organoids. Stem cell reports. 5(5):895–907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Au SH, Chamberlain MD, Mahesh S, Sefton MV, Wheeler AR (2014) Hepatic organoids for microfluidic drug screening. Lab Chip 14(17):3290–3299

    Article  CAS  PubMed  Google Scholar 

  30. Huch M, Boj SF, Clevers H (2013) Lgr5(+) liver stem cells, hepatic organoids and regenerative medicine. Regener medicine. 8(4):385–387

    Article  CAS  Google Scholar 

  31. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292(5819):154–156

    Article  CAS  PubMed  Google Scholar 

  32. 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

    Article  CAS  PubMed  Google Scholar 

  33. •Willyard C. The boom in mini stomachs, brains, breasts, kidneys and more. Nature. 2015;523(7562):520-2. Reviews the generation of mini-organs in a dish

  34. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME et al (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373–379

    Article  CAS  PubMed  Google Scholar 

  35. Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T et al (2013) Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499(7459):481–484

    Article  CAS  PubMed  Google Scholar 

  36. McCracken KW, Cata EM, Crawford CM, Sinagoga KL, Schumacher M, Rockich BE et al (2014) Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516(7531):400–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C et al (2015) Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526(7574):564–568

    Article  CAS  PubMed  Google Scholar 

  38. Raikwar SP, Kim EM, Sivitz WI, Allamargot C, Thedens DR, Zavazava N (2015) Human iPS cell-derived insulin producing cells form vascularized organoids under the kidney capsules of diabetic mice. PLoS One 10(1):e0116582

    Article  PubMed  PubMed Central  Google Scholar 

  39. Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE (2010) Reconstituting organ-level lung functions on a chip. Science 328(5986):1662–1668

    Article  CAS  PubMed  Google Scholar 

  40. Nunes SS, Miklas JW, Liu J, Aschar-Sobbi R, Xiao Y, Zhang B et al (2013) Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat Methods 10(8):781–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xiao Y, Zhang B, Liu H, Miklas JW, Gagliardi M, Pahnke A et al (2014) Microfabricated perfusable cardiac biowire: a platform that mimics native cardiac bundle. Lab Chip 14(5):869–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Labouesse M (2012) Role of the extracellular matrix in epithelial morphogenesis: a view from C. elegans. Organogenesis. Organogenesis 8(2):65–70

    Article  PubMed  PubMed Central  Google Scholar 

  43. Chan BP, Leong KW (2008) Scaffolding in tissue engineering: general approaches and tissue-specific considerations. Eur spine J 17(Suppl 4):467–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Song JJ, Ott HC (2011) Organ engineering based on decellularized matrix scaffolds. Trends Mol Med. 17(8):424–432

    Article  CAS  PubMed  Google Scholar 

  45. Guyette JP, Charest JM, Mills RW, Jank BJ, Moser PT, Gilpin SE et al (2016) Bioengineering human myocardium on native extracellular matrix. Circ Res 118(1):56–72

    Article  CAS  PubMed  Google Scholar 

  46. Dhandayuthapani B, Yoshida Y, Maekawa T, Kumar S. Polymeric Scaffolds in Tissue Engineering Application: A Review. International journal of polymer science. 2011;2011

  47. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB (2006) Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 367(9518):1241–1246

    Article  PubMed  Google Scholar 

  48. Nicodemus GD, Bryant SJ (2008) Cell encapsulation in biodegradable hydrogels for tissue engineering applications. Tissue Eng Part B 14(2):149–165

    Article  CAS  Google Scholar 

  49. Murphy SV, Atala A (2014) 3D bioprinting of tissues and organs. Nat Biotechnol 32(8):773–785

    Article  CAS  PubMed  Google Scholar 

  50. Cardoso MJ, Costa RR, Mano JF (2016) Marine origin polysaccharides in drug delivery systems. Marine Drugs 14(2):34

    Article  PubMed Central  Google Scholar 

  51. Silva TH, Moreira-Silva J, Marques AL, Domingues A, Bayon Y, Reis RL (2014) Marine origin collagens and its potential applications. Marine Drugs. 12(12):5881–5901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Guillemin G, Patat JL, Fournie J, Chetail M (1987) The use of coral as a bone graft substitute. J Biomed Mater Res 21(5):557–567

    Article  CAS  PubMed  Google Scholar 

  53. •• Kang HW, Lee SJ, Ko IK, Kengla C, Yoo JJ, Atala A. A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nature biotechnology. 2016. Generated 3D free-form shapes with multiple types of cells and biomaterials

  54. •• Zhang B, Montgomery M, Chamberlain MD, Ogawa S, Korolj A, Pahnke A, et al. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis. Nature materials. 2016 Generated the first organ-on-chip with a fully integrated 3D microvasculature

  55. •• Todhunter ME, Jee NY, Hughes AJ, Coyle MC, Cerchiari A, Farlow J, et al. Programmed synthesis of three-dimensional tissues. Nature methods. 2015;12(10):975-81 Reconstituted organoid-like tissues having a programmed size, shape, composition and spatial heterogeneity

  56. Svendsen CN (2013) Back to the future: how human induced pluripotent stem cells will transform regenerative medicine. Hum Mol Genet 22(R1):R32–R38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chen J, Lansford R, Stewart V, Young F, Alt FW (1993) RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development. Proc Natl Acad Sci USA 90(10):4528–4532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. •• Matsunari H, Nagashima H, Watanabe M, Umeyama K, Nakano K, Nagaya M, et al. Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(12):4557-62. Generated a functional pig pancreas using somatic cell cloning technology in pancreatogenesis-disabled porcine embryos

  59. Hermeren G (2015) Ethical considerations in chimera research. Development. 142(1):3–5

    Article  CAS  PubMed  Google Scholar 

  60. Hoppo T, Komori J, Manohar R, Stolz DB, Lagasse E (2011) Rescue of lethal hepatic failure by hepatized lymph nodes in mice. Gastroenterology 140(2):656–666

    Article  CAS  PubMed  Google Scholar 

  61. Komori J, Boone L, DeWard A, Hoppo T, Lagasse E (2012) The mouse lymph node as an ectopic transplantation site for multiple tissues. Nat Biotechnol 30(10):976–983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Francipane MG, Chandler J, Lagasse E (2013) Selective targeting of human colon cancer stem-like cells by the mTOR inhibitor Torin-1. Oncotarget 4(11):1948–1962

    Article  PubMed  PubMed Central  Google Scholar 

  63. Francipane MG, Lagasse E (2014) Maturation of embryonic tissues in a lymph node: a new approach for bioengineering complex organs. Organogenesis. 10(3):323–331

    Article  PubMed  Google Scholar 

  64. Francipane MG, Lagasse E (2015) The lymph node as a new site for kidney organogenesis. Stem Cells Transl Med. 4(3):295–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lawenda BD, Mondry TE, Johnstone PA (2009) Lymphedema: a primer on the identification and management of a chronic condition in oncologic treatment. CA Cancer J Clin 59(1):8–24

    Article  PubMed  Google Scholar 

  66. Suto H, Katakai T, Sugai M, Kinashi T, Shimizu A (2009) CXCL13 production by an established lymph node stromal cell line via lymphotoxin-beta receptor engagement involves the cooperation of multiple signaling pathways. Int Immunol 21(4):467–476

    Article  CAS  PubMed  Google Scholar 

  67. Li L, Cole J, Margolin DA (2013) Cancer stem cell and stromal microenvironment. Ochsner J 13(1):109–118

    PubMed  PubMed Central  Google Scholar 

  68. Spradling A, Drummond-Barbosa D, Kai T (2001) Stem cells find their niche. Nature 414(6859):98–104

    Article  CAS  PubMed  Google Scholar 

  69. • Sasai Y. Next-generation regenerative medicine: organogenesis from stem cells in 3D culture. Reviews the spatiotemporal control of dynamic cellular interactions. Cell stem cell. 2013;12(5):520-30.Reviews the spatiotemporal control of dynamic cellular interactions

  70. Atala A, Kasper FK, Mikos AG (2012) Engineering complex tissues. Sci Transl Med 4(160):60rv12

    Article  Google Scholar 

  71. Bhatia SN, Ingber DE (2014) Microfluidic organs-on-chips. Nat Biotechnol 32(8):760–772

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Ri.MED Foundation (M.G.F.) and the McGowan Institute for Regenerative Medicine (E.L.). We thank Julie Cramer and Aaron DeWard for providing images of intestine and esophageal organoids, respectively, and Lynda Guzik for proofreading and editing.

Author information

Authors and Affiliations

  1. McGowan Institute for Regenerative Medicine, Department of Pathology, University of Pittsburgh School of Medicine, Bridgeside Point II. 450 Technology Drive. Suite 333, Pittsburgh, PA, 15219, USA

    Maria Giovanna Francipane & Eric Lagasse

  2. Ri.MED Foundation, 90133, Palermo, Italy

    Maria Giovanna Francipane

Authors
  1. Maria Giovanna Francipane
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric Lagasse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Giovanna Francipane.

Ethics declarations

Conflict of Interest

Maria Giovanna Francipane and Eric Lagasse declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical collection on Tissue Engineering and Regenerative Medicine: Organogenesis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Francipane, M.G., Lagasse, E. Toward Organs on Demand: Breakthroughs and Challenges in Models of Organogenesis. Curr Pathobiol Rep 4, 77–85 (2016). https://doi.org/10.1007/s40139-016-0111-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40139-016-0111-9

Keywords

Search

Navigation