Skip to main content
SpringerLink
Log in

Various Three-Dimensional Culture Methods and Cell Types for Exosome Production

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

Abstract

Cell-based therapies have been used as promising treatments for several untreatable diseases. However, cell-based therapies have side effects such as tumorigenesis and immune responses. To overcome these side effects, therapeutic effects of exosomes have been researched as replacements for cell-based therapies. In addition, exosomes reduced the risk that can be induced by cell-based therapies. Exosomes contain biomolecules such as proteins, lipids, and nucleic acids that play an essential role in cell–cell and cell–matrix interactions during biological processes. Since the introduction of exosomes, those have been proven perpetually as one of the most effective and therapeutic methods for incurable diseases. Much research has been conducted to enhance the properties of exosomes, including immune regulation, tissue repair, and regeneration. However, yield rate of exosomes is the critical obstacle that should be overcome for practical cell-free therapy. Three-dimensional (3D) culture methods are introduced as a breakthrough to get higher production yields of exosomes. For example, hanging drop and microwell were well known 3D culture methods and easy to use without invasiveness. However, these methods have limitation in mass production of exosomes. Therefore, a scaffold, spinner flask, and fiber bioreactor were introduced for mass production of exosomes isolated from various cell types. Furthermore, exosomes treatments derived from 3D cultured cells showed enhanced cell proliferation, angiogenesis, and immunosuppressive properties. This review provides therapeutic applications of exosomes using 3D culture methods.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kusuma GD, Carthew J, Lim R, Frith JE. Effect of the microenvironment on mesenchymal stem cell paracrine signaling: opportunities to engineer the therapeutic effect. Stem Cells Dev. 2017;26:617–31.

    CAS  PubMed  Google Scholar 

  2. Kalra H, Drummen GP, Mathivanan S. Focus on extracellular vesicles: introducing the next small big thing. Int J Mol Sci. 2016;17:170.

    PubMed  PubMed Central  Google Scholar 

  3. Gurung S, Perocheau D, Touramanidou L, Baruteau J. The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun Signal. 2021;19:47.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9:19.

    PubMed  PubMed Central  Google Scholar 

  5. Huang X, Yuan T, Tschannen M, Sun Z, Jacob H, Du M, et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics. 2013;14:1–14.

    Google Scholar 

  6. Hade MD, Suire CN, Suo Z. Mesenchymal stem cell-derived exosomes: applications in regenerative medicine. Cells. 2021;10:1959.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhang B, Wang M, Gong A, Zhang X, Wu X, Zhu Y, et al. HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem cells. 2015;33:2158–68.

    CAS  PubMed  Google Scholar 

  8. Long Q, Upadhya D, Hattiangady B, Kim DK, An SY, Shuai B, et al. Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus. Proc Natl Acad Sci U S A. 2017;114:E3536–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Katsuda T, Tsuchiya R, Kosaka N, Yoshioka Y, Takagaki K, Oki K, et al. Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep. 2013;3:1197.

    PubMed  PubMed Central  Google Scholar 

  10. Dai S, Wei D, Wu Z, Zhou X, Wei X, Huang H, et al. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther. 2008;16:782–90.

    CAS  PubMed  Google Scholar 

  11. Haraszti RA, Miller R, Stoppato M, Sere YY, Coles A, Didiot MC, et al. Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity. Mol Ther. 2018;26:2838–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Yamada KM, Cukierman E. Modeling tissue morphogenesis and cancer in 3D. Cell. 2007;130:601–10.

    CAS  PubMed  Google Scholar 

  13. Shri M, Agrawal H, Rani P, Singh D, Onteru SK. Hanging drop, a best three-dimensional (3D) culture method for primary buffalo and sheep hepatocytes. Sci Rep. 2017;7:1203.

    PubMed  PubMed Central  Google Scholar 

  14. Gidrol X, Fouqué B, Ghenim L, Haguet V, Picollet-D’hahan N, Schaack B. 2D and 3D cell microarrays in pharmacology. Curr Opinion Pharmacol. 2009;9:664–8.

    CAS  Google Scholar 

  15. Todorov L, VadeBoncouer T. Etiology and use of the “hanging drop” technique: A review. Pain Res Treat. 2014;2014:146750.

    PubMed  PubMed Central  Google Scholar 

  16. Foglietta F, Canaparo R, Muccioli G, Terreno E, Serpe L. Methodological aspects and pharmacological applications of three-dimensional cancer cell cultures and organoids. Life Sci. 2020;254:117784.

    CAS  PubMed  Google Scholar 

  17. Yu W, Li S, Guan X, Zhang N, Xie X, Zhang K, et al. Higher yield and enhanced therapeutic effects of exosomes derived from MSCs in hydrogel-assisted 3D culture system for bone regeneration. Biomater Adv. 2022;133:112646.

    PubMed  Google Scholar 

  18. Cao J, Wang B, Tang T, Lv L, Ding Z, Li Z, et al. Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury. Stem Cell Res Ther. 2020;11:206.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Thippabhotla S, Zhong C, He M. 3D cell culture stimulates the secretion of in vivo like extracellular vesicles. Sci Rep. 2019;9:13012.

    PubMed  PubMed Central  Google Scholar 

  20. Lei Y, Schaffer DV. A fully defined and scalable 3D culture system for human pluripotent stem cell expansion and differentiation. Proc Natl Acad Sci U S A. 2013;110:E5039–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Faruqu FN, Liam-Or R, Zhou S, Nip R, Al-Jamal KT. Defined serum-free three-dimensional culture of umbilical cord-derived mesenchymal stem cells yields exosomes that promote fibroblast proliferation and migration in vitro. FASEB J. 2021;35:e21206.

    CAS  PubMed  Google Scholar 

  22. Moshksayan K, Kashaninejad N, Warkiani ME, Lock JG, Moghadas H, Firoozabadi B, et al. Spheroids-on-a-chip: Recent advances and design considerations in microfluidic platforms for spheroid formation and culture. Sens Actuators B Chem. 2018;263:151–76.

    CAS  Google Scholar 

  23. Ryu NE, Lee SH, Park H. Spheroid culture system methods and applications for mesenchymal stem cells. Cells. 2019;8:1620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. De Groot T, Veserat K, Berthier E, Beebe D, Theberge A. Surface-tension driven open microfluidic platform for hanging droplet culture. Lab Chip. 2016;16:334–44.

    PubMed  PubMed Central  Google Scholar 

  25. Timmins NE, Nielsen LK. Generation of multicellular tumor spheroids by the hanging-drop method. Methods Mol Med. 2007;140:141–51.

    Google Scholar 

  26. Kim M, Yun HW, Park DY, Choi BH, Min BH. Three-dimensional spheroid culture increases exosome secretion from mesenchymal stem cells. Tissue Eng Regen Med. 2018;15:427–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Giusti I, Poppa G, D’Ascenzo S, Esposito L, Vitale AR, Calvisi G, et al. Cancer three-dimensional spheroids mimic in vivo tumor features, displaying “inner” extracellular vesicles and vasculogenic mimicry. Int J Mol Sci. 2022;23:11782.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Manzoor AA, Romita L, Hwang DK. A review on microwell and microfluidic geometric array fabrication techniques and its potential applications in cellular studies. Can J Chem Eng. 2021;99:61–96.

    CAS  Google Scholar 

  29. Faruqu FN, Zhou S, Sami N, Gheidari F, Lu H, Al-Jamal KT. Three-dimensional culture of dental pulp pluripotent-like stem cells (DPPSCs) enhances Nanog expression and provides a serum-free condition for exosome isolation. FASEB BioAdv. 2020;2:419–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Huang R, Wang J, Chen H, Shi X, Wang X, Zhu Y, et al. The topography of fibrous scaffolds modulates the paracrine function of Ad-MSCs in the regeneration of skin tissues. Biomater Sci. 2019;7:4248–59.

    CAS  PubMed  Google Scholar 

  31. Su N, Gao P-L, Wang K, Wang J-Y, Zhong Y, Luo Y. Fibrous scaffolds potentiate the paracrine function of mesenchymal stem cells: A new dimension in cell-material interaction. Biomaterials. 2017;141:74–85.

    CAS  PubMed  Google Scholar 

  32. Fukuda J, Khademhosseini A, Yeo Y, Yang X, Yeh J, Eng G, et al. Micromolding of photocrosslinkable chitosan hydrogel for spheroid microarray and co-cultures. Biomaterials. 2006;27:5259–67.

    CAS  PubMed  Google Scholar 

  33. Han M, Yang H, Lu X, Li Y, Liu Z, Li F, et al. Three-dimensional-cultured MSC-derived exosome-hydrogel hybrid microneedle array patch for spinal cord repair. Nano Lett. 2022;22:6391–401.

    CAS  PubMed  Google Scholar 

  34. Han M, Zhang Z, Liu Z, Liu Y, Zhao H, Wang B, et al. Three-dimensional-cultured MSC-derived exosome with hydrogel for cerebral ischemia repair. Biomater Adv. 2023;149:213396.

    CAS  PubMed  Google Scholar 

  35. Liu X, Holzwarth JM, Ma PX. Functionalized synthetic biodegradable polymer scaffolds for tissue engineering. Macromol Biosci. 2012;12:911–9.

    CAS  PubMed  Google Scholar 

  36. Xie Y, Kawazoe N, Yang Y, Chen G. Preparation of mesh-like collagen scaffolds for tissue engineering. Mater Adv. 2022;3:1556–64.

    CAS  Google Scholar 

  37. Gao W, Liang T, He R, Ren J, Yao H, Wang K, et al. Exosomes from 3D culture of marrow stem cells enhances endothelial cell proliferation, migration, and angiogenesis via activation of the HMGB1/AKT pathway. Stem Cell Res. 2021;50:102122.

    CAS  Google Scholar 

  38. Yang L, Zhai Y, Hao Y, Zhu Z, Cheng G. The regulatory functionality of exosomes derived from hUMSCs in 3D culture for Alzheimer’s disease therapy. Small. 2020;16:e1906273.

    CAS  Google Scholar 

  39. Gloeckner H, Jonuleit T, Lemke H-D. Monitoring of cell viability and cell growth in a hollow-fiber bioreactor by use of the dye Alamar Blue. J Immunol Methods. 2001;252:131–8.

    CAS  PubMed  Google Scholar 

  40. Yan L, Wu X. Exosomes produced from 3D cultures of umbilical cord mesenchymal stem cells in a hollow-fiber bioreactor show improved osteochondral regeneration activity. Cell Biol Toxicol. 2020;36:165–78.

    CAS  PubMed  Google Scholar 

  41. Clément V, Roy V, Paré B, Goulet CR, Deschênes LT, Berthod F, et al. Tridimensional cell culture of dermal fibroblasts promotes exosome-mediated secretion of extracellular matrix proteins. Sci Rep. 2022;12:19786.

    PubMed  PubMed Central  Google Scholar 

  42. Hu S, Li Z, Cores J, Huang K, Su T, Dinh PU, et al. Needle-free injection of exosomes derived from human dermal fibroblast spheroids ameliorates skin photoaging. ACS Nano. 2019;13:11273–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Jovic D, Yu Y, Wang D, Wang K, Li H, Xu F, et al. A brief overview of global trends in MSC-based cell therapy. Stem Cell Rev Rep. 2022;18:1525–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.

    CAS  PubMed  Google Scholar 

  45. Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, et al. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem cells. 2004;22:1330–7.

    PubMed  Google Scholar 

  46. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Afizah H, Yang Z, Hui JH, Ouyang H-W, Lee E-H. A comparison between the chondrogenic potential of human bone marrow stem cells (BMSCs) and adipose-derived stem cells (ADSCs) taken from the same donors. Tissue Eng. 2007;13:659–66.

    CAS  PubMed  Google Scholar 

  48. Huang JI, Kazmi N, Durbhakula MM, Hering TM, Yoo JU, Johnstone B. Chondrogenic potential of progenitor cells derived from human bone marrow and adipose tissue: A patient-matched comparison. J Orthop Res. 2005;23:1383–9.

    CAS  PubMed  Google Scholar 

  49. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E, et al. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev. 2013;22:772–80.

    CAS  PubMed  Google Scholar 

  51. Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem cells. 2013;31:2737–46.

    CAS  PubMed  Google Scholar 

  52. Feng Y, Huang W, Wani M, Yu X, Ashraf M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One. 2014;9:e88685.

    PubMed  PubMed Central  Google Scholar 

  53. Del Fattore A, Luciano R, Saracino R, Battafarano G, Rizzo C, Pascucci L, et al. Differential effects of extracellular vesicles secreted by mesenchymal stem cells from different sources on glioblastoma cells. Expert Opin Biol Ther. 2015;15:495–504.

    PubMed  Google Scholar 

  54. Lopez-Verrilli MA, Caviedes A, Cabrera A, Sandoval S, Wyneken U, Khoury M. Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth. Neuroscience. 2016;320:129–39.

    CAS  PubMed  Google Scholar 

  55. Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem cells. 2017;35:851–8.

    CAS  PubMed  Google Scholar 

  56. Zhang L, Jiao G, Ren S, Zhang X, Li C, Wu W, et al. Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion. Stem Cell Res Ther. 2020;11:38.

    PubMed  PubMed Central  Google Scholar 

  57. Feng Y, Ke J, Cao P, Deng M, Li J, Cai H, et al. HMGB1-induced angiogenesis in perforated disc cells of human temporomandibular joint. J Cell Mol Med. 2018;22:1283–91.

    CAS  PubMed  Google Scholar 

  58. Dinh PUC, Paudel D, Brochu H, Popowski KD, Gracieux MC, Cores J, et al. Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis. Nat Commun. 2020;11:1064.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Romanov YA, Volgina N, Vtorushina V, Romanov AY, Dugina T, Kabaeva N, et al. Comparative analysis of secretome of human umbilical cord-and bone marrow-derived multipotent mesenchymal stromal cells. Bull Exp Biol Med. 2019;166:535–40.

    CAS  PubMed  Google Scholar 

  60. Ding M, Shen Y, Wang P, Xie Z, Xu S, Zhu Z, et al. Exosomes isolated from human umbilical cord mesenchymal stem cells alleviate neuroinflammation and reduce amyloid-beta deposition by modulating microglial activation in Alzheimer’s disease. Neurochem Res. 2018;43:2165–77.

    CAS  PubMed  Google Scholar 

  61. Cui GH, Wu J, Mou FF, Xie WH, Wang FB, Wang QL, et al. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J. 2018;32:654–68.

    CAS  PubMed  Google Scholar 

  62. Anttonen T, Kirjavainen A, Belevich I, Laos M, Richardson WD, Jokitalo E, et al. Cdc42-dependent structural development of auditory supporting cells is required for wound healing at adulthood. Sci Rep. 2012;2:978.

    PubMed  PubMed Central  Google Scholar 

  63. Kitajima Y, Luo L, Yan C, Tateishi S, Ono Y, Urata Y, et al. Potency of umbilical cord blood-and Wharton’s jelly-derived mesenchymal stem cells for scarless wound healing. Sci Rep. 2016;6:18844.

    PubMed  PubMed Central  Google Scholar 

  64. Zelman-Toister E, Bakos E, Cohen S, Zigmond E, Shezen E, Grabovsky V, et al. CD151 regulates T-cell migration in health and inflammatory bowel disease. Inflamm Bowel Dis. 2016;22:257–67.

    PubMed  Google Scholar 

  65. Wang XJ, Han G, Owens P, Siddiqui Y, Li AG. Role of TGFβ-mediated inflammation in cutaneous wound healing. J Investig Dermatol Symp Proc. 2006;11:112–7.

    CAS  PubMed  Google Scholar 

  66. Camões SP, Bulut O, Yazar V, Gaspar MM, Simões S, Ferreira R, et al. 3D-MSCs A151 ODN-loaded exosomes are immunomodulatory and reveal a proteomic cargo that sustains wound resolution. J Adv Res. 2022;41:113–28.

    PubMed  PubMed Central  Google Scholar 

  67. Guo SA, Dipietro LA. Factors affecting wound healing. J Dent Res. 2010;89:219–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ren Y, Liu J, Xu H, Wang S, Li S, Xiang M, et al. Knockout of integrin β1 in induced pluripotent stem cells accelerates skin-wound healing by promoting cell migration in extracellular matrix. Stem Cell Res Ther. 2022;13:389.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Miceli V, Pampalone M, Vella S, Carreca AP, Amico G, Conaldi PG. Comparison of immunosuppressive and angiogenic properties of human amnion-derived mesenchymal stem cells between 2D and 3D culture systems. Stem cells Int. 2019;2019:7486279.

    PubMed  PubMed Central  Google Scholar 

  70. Barlow S, Brooke G, Chatterjee K, Price G, Pelekanos R, Rossetti T, et al. Comparison of human placenta-and bone marrow–derived multipotent mesenchymal stem cells. Stem Cells Dev. 2008;17:1095–108.

    CAS  PubMed  Google Scholar 

  71. Bilic G, Zeisberger SM, Mallik AS, Zimmermann R, Zisch AH. Comparative characterization of cultured human term amnion epithelial and mesenchymal stromal cells for application in cell therapy. Cell Transplant. 2008;17:955–68.

    PubMed  Google Scholar 

  72. Shu J, He X, Li H, Liu X, Qiu X, Zhou T, et al. The beneficial effect of human amnion mesenchymal cells in inhibition of inflammation and induction of neuronal repair in EAE mice. J Immunol Res. 2018;2018:5083797.

    PubMed  PubMed Central  Google Scholar 

  73. Tuca AC, Ertl J, Hingerl K, Pichlsberger M, Fuchs J, Wurzer P, et al. Comparison of matrigel and matriderm as a carrier for human amnion-derived mesenchymal stem cells in wound healing. Placenta. 2016;48:99–103.

    CAS  PubMed  Google Scholar 

  74. Shen WC, Lai YC, Li LH, Liao K, Lai HC, Kao SY, et al. Methylation and PTEN activation in dental pulp mesenchymal stem cells promotes osteogenesis and reduces oncogenesis. Nat Commun. 2019;10:2226.

    PubMed  PubMed Central  Google Scholar 

  75. Alge DL, Zhou D, Adams LL, Wyss BK, Shadday MD, Woods EJ, et al. Donor-matched comparison of dental pulp stem cells and bone marrow-derived mesenchymal stem cells in a rat model. J Tissue Eng Regen Med. 2010;4:73–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Shen Z, Kuang S, Zhang Y, Yang M, Qin W, Shi X, et al. Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism. Bioact Mater. 2020;5:1113–26.

    PubMed  PubMed Central  Google Scholar 

  77. Zhuang Z, Yoshizawa-Smith S, Glowacki A, Maltos K, Pacheco C, Shehabeldin M, et al. Induction of M2 macrophages prevents bone loss in murine periodontitis models. J Dent Res. 2019;98:200–8.

    CAS  PubMed  Google Scholar 

  78. Zhang Y, Chen J, Fu H, Kuang S, He F, Zhang M, et al. Exosomes derived from 3D-cultured MSCs improve therapeutic effects in periodontitis and experimental colitis and restore the Th17 cell/Treg balance in inflamed periodontium. Int J Oral Sci. 2021;13:43.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Suh JS, Lee SH, Fouladian Z, Lee JY, Kim T, Kang MK, et al. Rosuvastatin prevents the exacerbation of atherosclerosis in ligature-induced periodontal disease mouse model. Sci Rep. 2020;10:6383.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Tian J, Zhu Q, Zhang Y, Bian Q, Hong Y, Shen Z, et al. Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate experimental colitis via modulating Th1/Th17 and Treg cell responses. Front Immunol. 2020;11:598322.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Zheng Y, Dong C, Yang J, Jin Y, Zheng W, Zhou Q, et al. Exosomal microRNA-155-5p from PDLSCs regulated Th17/Treg balance by targeting sirtuin-1 in chronic periodontitis. J Cell Physiol. 2019;234:20662–74.

    CAS  PubMed  Google Scholar 

  82. Yang G, Chen Q, Wen D, Chen Z, Wang J, Chen G, et al. A therapeutic microneedle patch made from hair-derived keratin for promoting hair regrowth. ACS Nano. 2019;13:4354–60.

    CAS  PubMed  Google Scholar 

  83. Enshell-Seijffers D, Lindon C, Kashiwagi M, Morgan BA. β-catenin activity in the dermal papilla regulates morphogenesis and regeneration of hair. Dev Cell. 2010;18:633–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Rajendran RL, Gangadaran P, Bak SS, Oh JM, Kalimuthu S, Lee HW, et al. Extracellular vesicles derived from MSCs activates dermal papilla cell in vitro and promotes hair follicle conversion from telogen to anagen in mice. Sci Rep. 2017;7:15560.

    PubMed  PubMed Central  Google Scholar 

  85. Higgins CA, Chen JC, Cerise JE, Jahoda CA, Christiano AM. Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth. Proc Natl Acad Sci U S A. 2013;110:19679–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang H, Zhu N-X, Huang K, Cai B-Z, Zeng Y, Xu Y-M, et al. iTRAQ-based quantitative proteomic comparison of early-and late-passage human dermal papilla cell secretome in relation to inducing hair follicle regeneration. PLoS One. 2016;11:e0167474.

    PubMed  PubMed Central  Google Scholar 

  87. Chen Y, Huang J, Chen R, Yang L, Wang J, Liu B, et al. Sustained release of dermal papilla-derived extracellular vesicles from injectable microgel promotes hair growth. Theranostics. 2020;10:1454–1478.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Hu S, Li Z, Lutz H, Huang K, Su T, Cores J, et al. Dermal exosomes containing miR-218–5p promote hair regeneration by regulating β-catenin signaling. Sci Adv. 2020;6:eaba1685.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ito Y, Hamazaki TS, Ohnuma K, Tamaki K, Asashima M, Okochi H. Isolation of murine hair-inducing cells using the cell surface marker prominin-1/CD133. J Invest Dermatol. 2007;127:1052–60.

    CAS  PubMed  Google Scholar 

  90. Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell. 2001;105:533–45.

    CAS  PubMed  Google Scholar 

  91. Zhou L, Wang H, Jing J, Yu L, Wu X, Lu Z. Morroniside regulates hair growth and cycle transition via activation of the Wnt/β-catenin signaling pathway. Sci Rep. 2018;8:13785.

    PubMed  PubMed Central  Google Scholar 

  92. Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, et al. Bone marrow–derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 2005;33:145–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001;105:369–77.

    CAS  PubMed  Google Scholar 

  94. Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002;297:2256–9.

    CAS  PubMed  Google Scholar 

  95. Bruscia EM, Ziegler EC, Price JE, Weiner S, Egan ME, Krause DS. Engraftment of donor-derived epithelial cells in multiple organs following bone marrow transplantation into newborn mice. Stem cells. 2006;24:2299–308.

    CAS  PubMed  Google Scholar 

  96. Henry E, Cores J, Hensley MT, Anthony S, Vandergriff A, de Andrade JB, et al. Adult lung spheroid cells contain progenitor cells and mediate regeneration in rodents with bleomycin-induced pulmonary fibrosis. Stem Cells Transl Med. 2015;4:1265–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Cores J, Dinh P-UC, Hensley T, Adler KB, Lobo LJ, Cheng K. A pre-investigational new drug study of lung spheroid cell therapy for treating pulmonary fibrosis. Stem Cells Transl Med. 2020;9:786–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Cores J, Hensley MT, Kinlaw K, Rikard SM, Dinh P-U, Paudel D, et al. Safety and efficacy of allogeneic lung spheroid cells in a mismatched rat model of pulmonary fibrosis. Stem Cells Transl Med. 2017;6:1905–16.

    PubMed  PubMed Central  Google Scholar 

  99. Dinh PU-C, Cores J, Hensley MT, Vandergriff AC, Tang J, Allen TA, et al. Derivation of therapeutic lung spheroid cells from minimally invasive transbronchial pulmonary biopsies. Respir Res. 2017;18:132.

    PubMed  PubMed Central  Google Scholar 

  100. Roach KM, Wulff H, Feghali-Bostwick C, Amrani Y, Bradding P. Increased constitutive αSMA and Smad2/3 expression in idiopathic pulmonary fibrosis myofibroblasts is KCa3. 1-dependent. Respir Res. 2014;15:155.

    PubMed  PubMed Central  Google Scholar 

  101. Jia L, Liu Y, Han Y, Zhou X, Wang F. Differential expression and inhibitory effects of aquaporins on the development of adenomyosis. Mol Med Rep. 2020;22:3840–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Gauldie J, Bonniaud P, Sime P, Ask K, Kolb M. TGF-β, Smad3 and the process of progressive fibrosis. Biochem Soc Trans. 2007;35:661–4.

    CAS  PubMed  Google Scholar 

  103. Harrington JR. The role of MCP-1 in atherosclerosis. Stem cells. 2000;18:65–6.

    CAS  PubMed  Google Scholar 

  104. Drost J, Clevers H. Organoids in cancer research. Nat Rev Cancer. 2018;18:407–18.

    CAS  PubMed  Google Scholar 

  105. Fatehullah A, Tan SH, Barker N. Organoids as an in vitro model of human development and disease. Nat Cell Biol. 2016;18:246–54.

    PubMed  Google Scholar 

  106. Ringuette-Goulet C, Bolduc S, Pouliot F. Modeling human bladder cancer. World J Urol. 2018;36:1759–66.

    PubMed  Google Scholar 

  107. Sachs N, Clevers H. Organoid cultures for the analysis of cancer phenotypes. Curr Opin Genet Dev. 2014;24:68–73.

    CAS  PubMed  Google Scholar 

  108. Tu J, Luo X, Liu H, Zhang J, He M. Cancer spheroids derived exosomes reveal more molecular features relevant to progressed cancer. Biochem Biophys Rep. 2021;26:101026.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ghafouri-Fard S, Khoshbakht T, Hussen BM, Taheri M, Samadian M. a review on the role of miR-1246 in the pathoetiology of different cancers. Front Mol Biosci. 2022;8:771835.

    PubMed  PubMed Central  Google Scholar 

  110. Pfeffer SR, Yang CH, Pfeffer LM. The role of miR-21 in cancer. Drug Dev Res. 2015;76:270–7.

    CAS  PubMed  Google Scholar 

  111. Wu Q, Luo G, Yang Z, Zhu F, An Y, Shi Y, et al. miR-17-5p promotes proliferation by targeting SOCS6 in gastric cancer cells. FEBS Lett. 2014;588:2055–62.

    CAS  PubMed  Google Scholar 

  112. Sun M, Liu XH, Li JH, Yang JS, Zhang EB, Yin DD, et al. MiR-196a is upregulated in gastric cancer and promotes cell proliferation by downregulating p27kip1. Mol Cancer Ther. 2012;11:842–52.

    CAS  PubMed  Google Scholar 

  113. Wang H, Hu H, Luo Z, Liu S, Wu W, Zhu M, et al. miR-4454 up-regulated by HPV16 E6/E7 promotes invasion and migration by targeting ABHD2/NUDT21 in cervical cancer. Biosci Rep. 2020;40:BSR20200796.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Naseri M, Zöller M, Hadjati J, Ghods R, Ranaei Pirmardan E, Kiani J, et al. Dendritic cells loaded with exosomes derived from cancer stem cell-enriched spheroids as a potential immunotherapeutic option. J Cell Mol Med. 2021;25:3312–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Ghosh S, Garg S, Ghosh S. Cell-derived exosome therapy: a novel approach to treat post-traumatic brain injury mediated neural injury. ACS Chem Neurosci. 2020;11:2045–7.

    CAS  PubMed  Google Scholar 

  116. Zhu M, Li Y, Shi J, Feng W, Nie G, Zhao Y. Exosomes as extrapulmonary signaling conveyors for nanoparticle-induced systemic immune activation. Small. 2012;8:404–12.

    CAS  PubMed  Google Scholar 

  117. Diaz-Armas GG, Cervantes-Gonzalez AP, Martinez-Duarte R, Perez-Gonzalez VH. Electrically driven microfluidic platforms for exosome manipulation and characterization. Electrophoresis. 2022;43:327–39.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF), and the Ministry of Science and ICT (NRF-2019R1C1C1007384, NRF-2020M2D9A3094171, and NRF-2021R1A4A1032782). This research was also supported by a Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Health & Welfare; project Number: 21A0102L1-12). Industrial Technology Alchemist Program funded by Ministry of Trade, Industry, and Energy (MOTIE) of Korea (20018560)

Author information

Author notes

  1. Dong-Hyun Lee and Dae Won Yun are co-first authors and contributed equally to this work.

Authors and Affiliations

  1. School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-Ro, Jangan-Gu, Suwon, Gyeonggi-Do, 16419, Republic of Korea

    Dong-Hyun Lee, Dae Won Yun, Yeong Hwan Kim, Gwang-Bum Im, Jiyu Hyun, Hyun Su Park & Suk Ho Bhang

  2. Department of Radiation Oncology, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea

    Sang Hyoun Choi

Authors
  1. Dong-Hyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dae Won Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yeong Hwan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gwang-Bum Im
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiyu Hyun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hyun Su Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Suk Ho Bhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sang Hyoun Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Suk Ho Bhang or Sang Hyoun Choi.

Ethics declarations

Conflict of interest

The authors declare no financial conflicts of interest.

Ethical statement

No experiments involving animals or humans were conducted in this study.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, DH., Yun, D.W., Kim, Y.H. et al. Various Three-Dimensional Culture Methods and Cell Types for Exosome Production. Tissue Eng Regen Med 20, 621–635 (2023). https://doi.org/10.1007/s13770-023-00551-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-023-00551-y

Keywords

Search

Navigation