Skip to main content
Log in

Cocktail Formula and Application Prospects for Oral and Maxillofacial Organoids

  • Review Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Oral and maxillofacial organoids (OMOs), tiny tissues and organs derived from stem cells cultured through 3-d cell culture models, can fully summarize the cell tissue structure, physiological functions and biological characteristics of the source tissues in the body. OMOs are applied in areas such as disease modelling, developmental and regenerative medicine, drug screening, personalized treatment, etc. Although the construction of organoids in various parts of the oral and maxillofacial (OM) region has achieved considerable success, the existing cocktail formulae (construction strategies) are not widely applicable for tissues of various sources due to factors including the heterogeneity of the source tissues and the dependence on laboratory technology. Most of their formulae are based on growth factor niches containing expensive recombinant proteins with their efficiency remaining to be improved. In view of this, the cocktail formulae of various parts of the OM organs are reviewed with further discussion of the application and prospects for those OMOs to find some affordable cocktail formula with strong operability and high repeatability for various maxillofacial organs. The results may help improve the efficiency of organoid construction in the laboratory and accelerate the pace of the clinical use of organoid technology.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References:

  1. Doss MX, Sachinidis A. Current challenges of iPSC-based disease modeling and therapeutic implications. Cells. 2019;8:403.

    Article  CAS  PubMed Central  Google Scholar 

  2. Fujii M, Sato T. Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases. Nat Mater. 2021;20:156–69.

    Article  CAS  PubMed  Google Scholar 

  3. Combes AN, Zappia L, Er PX, Oshlack A, Little MH. Single-cell analysis reveals congruence between kidney organoids and human fetal kidney. Genome Med. 2019;11:3.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Xu R, Zhou X, Wang S, Trinkle C. Tumor organoid models in precision medicine and investigating cancer-stromal interactions. Pharmacol Ther. 2021;218:107668.

    Article  CAS  PubMed  Google Scholar 

  5. Di Lullo E, Kriegstein AR. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. 2017;18:573–84.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Shinozawa T, Kimura M, Cai Y, Saiki N, Yoneyama Y, Ouchi R, et al. High-fidelity drug-induced liver injury screen using human pluripotent stem cell-derived organoids. Gastroenterology. 2021;160:831–46.e10.

    Article  CAS  PubMed  Google Scholar 

  7. Takahashi T. Organoids for drug discovery and personalized medicine. Annu Rev Pharmacol Toxicol. 2019;59:447–62.

    Article  CAS  PubMed  Google Scholar 

  8. Gonzalez GM, Cichon I, Scislowska-Czarnecka A, Kolaczkowska E. Challenges in 3D culturing of neutrophils: assessment of cell viability. J Immunol Methods. 2018;457:73–7.

    Article  Google Scholar 

  9. Liu HD, Xia BR, Jin MZ, Lou G. Organoid of ovarian cancer: genomic analysis and drug screening. Clin Transl Oncol. 2020;22:1240–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cristobal A, van den Toorn HWP, van de Wetering M, Clevers H, Heck AJR, Mohammed S. Personalized proteome profiles of healthy and tumor human colon organoids reveal both individual diversity and basic features of colorectal cancer. Cell Rep. 2017;18:263–74.

    Article  CAS  PubMed  Google Scholar 

  11. Murakami S, et al. Application of “tissueoid cell culture system” using a silicate fiber scaffold for cancer research. Pathobiology. 2020;87:291–301.

    Article  CAS  PubMed  Google Scholar 

  12. 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;459:262–5.

    Article  CAS  PubMed  Google Scholar 

  13. Lacruz RS, Habelitz S, Wright JT, Paine ML. Dental enamel formation and implications for oral health and disease. Physiol Rev. 2017;97:939–93.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Barlow LA, Klein OD. Developing and regenerating a sense of taste. Curr Top Dev Biol. 2015;111:401–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Larsen M, Yamada KM, Musselmann K. Systems analysis of salivary gland development and disease. Wiley Interdiscip Rev Syst Biol Med. 2010;2:670–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Suzuki A, Ogata K, Iwata J. Cell signaling regulation in salivary gland development. Cell Mol Life Sci. 2021;78:3299–315.

    Article  CAS  PubMed  Google Scholar 

  17. Knosp WM, Knox SM, Hoffman MP. Salivary gland organogenesis. Wiley Interdiscip Rev Dev Biol. 2012;1:69–82.

    Article  CAS  PubMed  Google Scholar 

  18. de Paula F, Teshima THN, Hsieh R, Souza MM, Nico MMS, Lourenco SV. Overview of human salivary glands: highlights of morphology and developing processes. Anat Rec (Hoboken). 2017;300:1180–8.

    Article  Google Scholar 

  19. Tanaka J, Takamatsu K, Yukimori A, Kujiraoka S, Ishida S, Takakura I, et al. Sox9 function in salivary gland development. J Oral Biosci. 2021;63:8–13.

    Article  CAS  PubMed  Google Scholar 

  20. Li J, Economou AD, Vacca B, Green JBA. Epithelial invagination by a vertical telescoping cell movement in mammalian salivary glands and teeth. Nat Commun. 2020;11:2366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jung JK, Jung HI, Neupane S, Kim KR, Kim JY, Yamamoto H, et al. Involvement of PI3K and PKA pathways in mouse tongue epithelial differentiation. Acta Histochem. 2017;119:92–8.

    Article  CAS  PubMed  Google Scholar 

  22. Chen KG, Mallon BS, McKay RD, Robey PG. Human pluripotent stem cell culture: considerations for maintenance, expansion, and therapeutics. Cell Stem Cell. 2014;14:13–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.

    Article  CAS  PubMed  Google Scholar 

  24. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–6.

    Article  CAS  PubMed  Google Scholar 

  25. Bradley A, Evans M, Kaufman MH, Robertson E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature. 1984;309:255–6.

    Article  CAS  PubMed  Google Scholar 

  26. Tiscornia G, Vivas EL, Izpisua BJ. Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat Med. 2011;17:1570–6.

    Article  CAS  PubMed  Google Scholar 

  27. Wang M, Zhang L, Gage FH. Modeling neuropsychiatric disorders using human induced pluripotent stem cells. Protein Cell. 2020;11:45–59.

    Article  CAS  PubMed  Google Scholar 

  28. Mora C, Serzanti M, Consiglio A, Memo M, Dell'Era P. Clinical potentials of human pluripotent stem cells. Cell Biol Toxicol. 2017;33:351–60.

    Article  CAS  PubMed  Google Scholar 

  29. Tanaka J, Ogawa M, Hojo H, Kawashima Y, Mabuchi Y, Hata K, et al. Generation of orthotopically functional salivary gland from embryonic stem cells. Nat Commun. 2018;9:4216.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Clevers H. Modeling development and disease with organoids. Cell. 2016;165:1586–97.

    Article  CAS  PubMed  Google Scholar 

  31. Yamanaka S. Pluripotent stem cell-based cell therapy-promise and challenges. Cell Stem Cell. 2020;27:523–31.

    Article  CAS  PubMed  Google Scholar 

  32. Cable J, Fuchs E, Weissman I, Jasper H, Glass D, Rando TA, et al. Adult stem cells and regenerative medicine-a symposium report. Ann N Y Acad Sci. 2020;1462:27–36.

    Article  PubMed  Google Scholar 

  33. Xu Y, Zhu H, Zhao D, Tan J. Endometrial stem cells: clinical application and pathological roles. Int J Clin Exp Med. 2015;8:22039–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Huch M, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015;160:299–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gurusamy N, Alsayari A, Rajasingh S, Rajasingh J. Adult stem cells for regenerative therapy. Prog Mol Biol Transl Sci. 2018;160:1–22.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang J, Jiao J. Molecular biomarkers for embryonic and adult neural stem cell and neurogenesis. Biomed Res Int. 2015;2015:727542.

    PubMed  PubMed Central  Google Scholar 

  37. Kleinman HK, Martin GR. Matrigel: basement membrane matrix with biological activity. Semin Cancer Biol. 2005;15:378–86.

    Article  CAS  PubMed  Google Scholar 

  38. Aisenbrey EA, Murphy WL. Synthetic alternatives to Matrigel. Nat Rev Mater. 2020;5:539–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Barry C, Schmitz MT, Propson NE, Hou Z, Zhang J, Nguyen BK, et al. Uniform neural tissue models produced on synthetic hydrogels using standard culture techniques. Exp Biol Med (Maywood). 2017;242:1679–89.

    Article  CAS  Google Scholar 

  40. Gilbert PM, Havenstrite KL, Magnusson KE, Sacco A, Leonardi NA, Kraft P, et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science. 2010;329:1078–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126:677–89.

    Article  CAS  PubMed  Google Scholar 

  42. Peters SB, Naim N, Nelson DA, Mosier AP, Cady NC, Larsen M. Biocompatible tissue scaffold compliance promotes salivary gland morphogenesis and differentiation. Tissue Eng Part A. 2014;20:1632–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015;161:933–45.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Driehuis E, Kolders S, Spelier S, Lõhmussaar K, Willems SM, Devriese LA, et al. Oral mucosal organoids as a potential platform for personalized cancer therapy. Cancer Discov. 2019;9:852–71.

    Article  CAS  PubMed  Google Scholar 

  45. Wu H, Uchimura K, Donnelly EL, Kirita Y, Morris SA, Humphreys BD. Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics. Cell Stem Cell. 2018;23:869-81.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tanaka T, Komai Y, Tokuyama Y, Yanai H, Ohe S, Okazaki K, et al. Identification of stem cells that maintain and regenerate lingual keratinized epithelial cells. Nat Cell Biol. 2013;15:511–8.

    Article  CAS  PubMed  Google Scholar 

  47. Luo X, Okubo T, Randell S, Hogan BL. Culture of endodermal stem/progenitor cells of the mouse tongue. In Vitro Cell Dev Biol Anim. 2009;45:44–54.

    Article  CAS  PubMed  Google Scholar 

  48. Hisha H, Tanaka T, Ueno H. Lingual epithelial stem cells and organoid culture of them. Int J Mol Sci. 2016;17:168.

    Article  PubMed Central  Google Scholar 

  49. Hisha H, Ueno H. Organoid culture of lingual epithelial cells in a three-dimensional matrix. Methods Mol Biol. 2019;1576:93–9.

    Article  CAS  PubMed  Google Scholar 

  50. Yee KK, Li Y, Redding KM, Iwatsuki K, Margolskee RF, Jiang P. Lgr5-EGFP marks taste bud stem/progenitor cells in posterior tongue. Stem Cells. 2013;31:992–1000.

    Article  CAS  PubMed  Google Scholar 

  51. Ren W, Lewandowski BC, Watson J, Aihara E, Iwatsuki K, Bachmanov AA, et al. Single Lgr5- or Lgr6-expressing taste stem/progenitor cells generate taste bud cells ex vivo. Proc Natl Acad Sci U S A. 2014;111:16401–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Aihara E, Mahe MM, Schumacher MA, Matthis AL, Feng R, Ren W, et al. Characterization of stem/progenitor cell cycle using murine circumvallate papilla taste bud organoid. Sci Rep. 2015;5:17185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nishiyama M, Yuki S, Fukano C, Sako H, Miyamoto T, Tomooka Y. Attempt to develop taste bud models in three-dimensional culture. Zoolog Sci. 2011;28:623–32.

    Article  CAS  PubMed  Google Scholar 

  54. Nanduri LS, 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 Reports. 2014;3:957–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pringle S, Maimets M, van der Zwaag M, Stokman MA, van Gosliga D, Zwart E, et al. Human salivary gland stem cells functionally restore radiation damaged salivary glands. Stem Cells. 2016;34:640–52.

    Article  CAS  PubMed  Google Scholar 

  56. Srinivasan PP, Patel VN, Liu S, Harrington DA, Hoffman MP, Jia X, et al. Primary salivary human stem/progenitor cells undergo microenvironment-driven acinar-like differentiation in hyaluronate hydrogel culture. Stem Cells Transl Med. 2017;6:110–20.

    Article  CAS  PubMed  Google Scholar 

  57. Athwal H, Lombaert I. 3D organoid formation from the murine salivary gland cell line SIMS. Bio Protoc. 2019;9:e3386.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ogawa M, Oshima M, Imamura A, Sekine Y, Ishida K, Yamashita K, et al. Functional salivary gland regeneration by transplantation of a bioengineered organ germ. Nat Commun. 2013;4:2498.

    Article  PubMed  Google Scholar 

  59. Shin HS, Hong HJ, Koh WG, Lim JY. Organotypic 3D culture in nanoscaffold microwells supports salivary gland stem-cell-based organization. ACS Biomater Sci Eng. 2018;4:4311–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang F, Li G, Wu Z, Fan Z, Yang M, Wu T, et al. Tracking diphyodont development in miniature pigs in vitro and in vivo. Biol Open. 2019;8:bio037036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kim EJ, Yoon KS, Arakaki M, Otsu K, Fukumoto S, Harada H, et al. Effective differentiation of induced pluripotent stem cells into dental cells. Dev Dyn. 2019;248:129–39.

    Article  PubMed  Google Scholar 

  62. Jeong SY, Lee S, Choi WH, Jee JH, Kim HR, Yoo J. Fabrication of Dentin-pulp-like organoids using dental-pulp stem cells. Cells. 2020;9:642.

  63. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

    Article  CAS  PubMed  Google Scholar 

  64. Zhao L, Huang L, Yu S, Zheng J, Wang H, Zhang Y. Decellularized tongue tissue as an in vitro model for studying tongue cancer and tongue regeneration. Acta Biomater. 2017;58:122–35.

    Article  CAS  PubMed  Google Scholar 

  65. Tam K, Schoppy DW, Shin JH, Tay JK, Moreno-Nieves U, Mundy DC, et al. Assessing the impact of targeting CEACAM1 in head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg. 2018;159:76–84.

    Article  PubMed  Google Scholar 

  66. Noi M, Mukaisho KI, Yoshida S, Murakami S, Koshinuma S, Adachi T, et al. ERK phosphorylation functions in invadopodia formation in tongue cancer cells in a novel silicate fibre-based 3D cell culture system. Int J Oral Sci. 2018;10:30.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Zhou J, Zhang Y. Cancer stem cells: models, mechanisms and implications for improved treatment. Cell Cycle. 2008;7:1360–70.

    Article  CAS  PubMed  Google Scholar 

  68. Zhao H, Hu CY, Chen WM, Huang P. Lactate promotes cancer stem-like property of oral sequamous cell carcinoma. Curr Med Sci. 2019;39:403–9.

    Article  PubMed  Google Scholar 

  69. Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, et al. Visualization and targeting of LGR5(+) human colon cancer stem cells. Nature. 2017;545:187–92.

    Article  CAS  PubMed  Google Scholar 

  70. Yoshimoto S, et al. Inhibition of Alk signaling promotes the induction of human salivary-gland-derived organoids. Dis Model Mech. 2020;13:dmm045054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pinnock A, Murdoch C, Moharamzadeh K, Whawell S, Douglas CW. Characterisation and optimisation of organotypic oral mucosal models to study Porphyromonas gingivalis invasion. Microbes Infect. 2014;16:310–9.

    Article  CAS  PubMed  Google Scholar 

  72. Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell. 2013;13:653–8.

    Article  CAS  PubMed  Google Scholar 

  73. Rosowski J, Bräunig J, Amler AK, Strietzel FP, Lauster R, Rosowski M. Emulating the early phases of human tooth development in vitro. Sci Rep. 2019;9:7057.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Zhu L, Zhang J, Xiao L, Liu S, Yu J, Chen W, et al. Autophagy in resin monomer-initiated toxicity of dental mesenchymal cells: a novel therapeutic target of N-acetyl cysteine. J Mater Chem B. 2015;3:6820–36.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

MO performed the majority of the writing; QL and XL performed data acquisition; JY performed the Data interpretation and Article design; XM performed the manuscript modification and verification. JY and XM contributed equally to this work and should be considered as co-corresponding authors. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jinguang Yao or Xiaoqiang Mo.

Ethics declarations

Conflict of interest

There is no conflict of interest associated with any of the senior author or other coauthors contributing their efforts in this manuscript.

Ethical statement

Ethical approval and consent to participate is not applicable to this article as no data were generated or analyzed during the current study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ou, M., Li, Q., Ling, X. et al. Cocktail Formula and Application Prospects for Oral and Maxillofacial Organoids. Tissue Eng Regen Med 19, 913–925 (2022). https://doi.org/10.1007/s13770-022-00455-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-022-00455-3

Keywords

Navigation