Skip to main content
SpringerLink
Log in

Mesenchymal Stem Cell Spheroids: A Promising Tool for Vascularized Tissue Regeneration

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

Abstract

Background

Mesenchymal stem cells (MSCs) are undifferentiated cells that can differentiate into specific cell lineages when exposed to the right conditions. The ability of MSCs to differentiate into particular cells is considered very important in biological research and clinical applications. MSC spheroids are clusters of MSCs cultured in three dimensions, which play an important role in enhancing the proliferation and differentiation of MSCs. MSCs can also participate in vascular formation by differentiating into endothelial cells and secreting paracrine factors. Vascularization ability is essential in impaired tissue repair and function recovery. Therefore, the vascularization ability of MSCs, which enhances angiogenesis and accelerates tissue healing has made MSCs a promising tool for tissue regeneration. However, MSC spheroids are a relatively new research field, and more research is needed to understand their full potential.

Methods

In this review, we highlight the importance of MSC spheroids’ vascularization ability in tissue engineering and regenerative medicine while providing the current status of studies on the MSC spheroids’ vascularization and suggesting potential future research directions for MSC spheroids.

Results

Studies both in vivo and in vitro have demonstrated MSC spheroids’ capacity to develop into endothelial cells and stimulate vasculogenesis.

Conclusion

MSC spheroids show potential to enhance vascularization ability in tissue regeneration. Yet, further research is required to comprehensively understand the relationship between MSC spheroids and vascularization mechanisms.

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

Data availability statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Henderson AR, Choi H, Lee E. Blood and lymphatic vasculatures on-chip platforms and their applications for organ-specific in vitro modeling. Micromachines. 2020;11:147.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6:389–95.

    Article  CAS  PubMed  Google Scholar 

  3. Wang Y, Kankala RK, Ou C, Chen A, Yang Z. Advances in hydrogel-based vascularized tissues for tissue repair and drug screening. Bioact Mater. 2022;9:198–220.

    CAS  PubMed  Google Scholar 

  4. Santos MI, Unger RE, Sousa RA, Reis RL, Kirkpatrick CJ. Crosstalk between osteoblasts and endothelial cells co-cultured on a polycaprolactone–starch scaffold and the in vitro development of vascularization. Biomaterials. 2009;30:4407–15.

    Article  CAS  PubMed  Google Scholar 

  5. Ruehle M, Eastburn E, LaBelle S, Krishnan L, Weiss J, Boerckel J, et al. Extracellular matrix compression temporally regulates microvascular angiogenesis. Sci Adv. 2020;6:eabb6351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Maacha S, Sidahmed H, Jacob S, Gentilcore G, Calzone R, Grivel JC, et al. Paracrine mechanisms of mesenchymal stromal cells in angiogenesis. Stem Cells Int. 2020;2020:4356359.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Jia P, Zhao X, Liu Y, Liu M, Zhang Q, Chen S, et al. The RGD-modified self-assembling D-form peptide hydrogel enhances the therapeutic effects of mesenchymal stem cells (MSC) for hindlimb ischemia by promoting angiogenesis. Chem Eng J. 2022;450:138004.

    Article  CAS  Google Scholar 

  8. Almalki SG, Agrawal DK. Key transcription factors in the differentiation of mesenchymal stem cells. Differentiation. 2016;92:41–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Griffin KH, Fok SW, Kent LJ. Strategies to capitalize on cell spheroid therapeutic potential for tissue repair and disease modeling. NPJ Regen Med. 2022;7:70.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Daly AC, Davidson MD, Burdick JA. 3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels. Nature Commun. 2021;12:753.

    Article  CAS  Google Scholar 

  11. Ayan B, Heo DN, Zhang Z, Dey M, Povilianskas A, Drapaca C, et al. Aspiration-assisted bioprinting for precise positioning of biologics. Sci Adv. 2020;6:5111.

    Article  Google Scholar 

  12. Ho SS, Hung BP, Heyrani N, Lee MA, Leach JK. Hypoxic preconditioning of mesenchymal stem cells with subsequent spheroid formation accelerates repair of segmental bone defects. Stem Cells. 2018;36:1393–403.

    Article  CAS  PubMed  Google Scholar 

  13. Ho SS, Murphy KC, Binder BY, Vissers CB, Leach JK. Increased survival and function of mesenchymal stem cell spheroids entrapped in instructive alginate hydrogels. Stem Cells Transl Med Stem Cells Transl Med. 2016;5:773–81.

    Article  CAS  PubMed  Google Scholar 

  14. Fang Y, Ji M, Wu B, Xu X, Wang G, Zhang Y, et al. Engineering highly vascularized bone tissues by 3D bioprinting of granular prevascularized spheroids. ACS Appl Mater Interfaces. 2023;15:43492–502.

    Article  CAS  PubMed  Google Scholar 

  15. Baer PC, Griesche N, Luttmann W, Schubert R, Luttmann A, Geiger H. Human adipose-derived mesenchymal stem cells in vitro: evaluation of an optimal expansion medium preserving stemness. Cytotherapy. 2010;12:96–106.

    Article  CAS  PubMed  Google Scholar 

  16. Lin RZ, Chou LF, Chien CCM, Chang HY. Dynamic analysis of hepatoma spheroid formation: roles of E-cadherin and β1-integrin. Cell Tissue Res. 2006;324:411–22.

    Article  CAS  PubMed  Google Scholar 

  17. 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;31:108–15.

    Article  CAS  PubMed  Google Scholar 

  18. Tseng TC, Wong CW, Hsieh FY, Hsu SH. Biomaterial substrate-mediated multicellular spheroid formation and their applications in tissue engineering. Biotechnol J. 2017;12:1700064.

    Article  Google Scholar 

  19. Yeh HY, Liu BH, Sieber M, Hsu SH. Substrate-dependent gene regulation of self-assembled human MSC spheroids on chitosan membranes. BMC Genom. 2014;15:10.

    Article  Google Scholar 

  20. Ezquerra S, Zuleta A, Arancibia R, Estay J, Aulestia F, Carrion F. Functional properties of human-derived mesenchymal stem cell spheroids: a meta-analysis and systematic review. Stem Cells Int. 2021;2021:8825332.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kaminska A, Wedzinska A, Kot M, Sarnowska A. Effect of long-term 3D spheroid culture on WJ-MSC. Cells. 2021;10:719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee SY, Lee JW. 3D Spheroid cultures of stem cells and exosome applications for cartilage repair. Life. 2022;12:939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cheng NC, Chen SY, Li JR, Young TH. Short-term spheroid formation enhances the regenerative capacity of adipose-derived stem cells by promoting stemness, angiogenesis, and chemotaxis. Stem Cells Transl Med. 2013;2:584–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ratushnyy A, Ezdakova M, Buravkova L. Secretome of senescent adipose-derived mesenchymal stem cells negatively regulates angiogenesis. Int J Mol Sci. 2020;21:1802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Redondo-Castro E, Cunningham CJ, Miller J, Brown H, Allan SM, Pinteaux E. Changes in the secretome of tri-dimensional spheroid-cultured human mesenchymal stem cells in vitro by interleukin-1 priming. Stem Cell Res Ther. 2018;9:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hsu TW, Lu YJ, Lin YJ, Huang YT, Hsieh LH, Wu BH, et al. Transplantation of 3D MSC/HUVEC spheroids with neuroprotective and proangiogenic potentials ameliorates ischemic stroke brain injury. Biomaterials. 2021;272:120765.

    Article  CAS  PubMed  Google Scholar 

  27. Gangadaran P, Oh EJ, Rajendran RL, Oh JM, Kim HM, Kwak S, et al. Three-dimensional culture conditioned bone marrow MSC secretome accelerates wound healing in a burn injury mouse model. Biochem Biophys Res Commun. 2023;673:87–95.

    Article  CAS  PubMed  Google Scholar 

  28. Vestweber D. VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb Vasc Biol. 2008;28:223–32.

    Article  CAS  PubMed  Google Scholar 

  29. Gao C, Zhang Y, Xie J, Wang X, Cao L, Chen G, et al. VE-cadherin functionalized injectable PAMAM/HA hydrogel promotes endothelial differentiation of hMSCs and vascularization. Appl Mater Today. 2020;20:100690.

    Article  Google Scholar 

  30. Wang H, Li X, Lai S, Cao Q, Liu Y, Li J, et al. Construction of vascularized tissue engineered bone with nHA-coated BCP bioceramics loaded with peripheral blood-derived MSC and EPC to repair large segmental femoral bone defect. ACS Appl Mater Interfaces. 2023;15:249–64.

    Article  CAS  PubMed  Google Scholar 

  31. Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, et al. Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappaB signaling. Stem Cells. 2016;34:601–13.

    Article  CAS  PubMed  Google Scholar 

  32. Kelly-Goss MR, Sweat RS, Stapor PC, Peirce SM, Murfee WL. Targeting pericytes for angiogenic therapies. Microcirculation. 2014;21:345–57.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Thomas HM, Cowin AJ, Mills SJ. The importance of pericytes in healing: wounds and other pathologies. Int J Mol Sci. 2017;18:1129.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Shah S, Kang KT. Two-cell spheroid angiogenesis assay system using both endothelial colony forming cells and mesenchymal stem cells. Biomol Ther. 2018;26:474–80.

    Article  CAS  Google Scholar 

  35. Shologu N, Scully M, Laffey JG, O’Toole D. Human mesenchymal stem cell secretome from bone marrow or adipose-derived tissue sources for treatment of hypoxia-induced pulmonary epithelial injury. Int J Mol Sci. 2018;19:2996.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Bhang SH, Cho SW, La WG, Lee TJ, Yang HS, Sun AY, et al. Angiogenesis in ischemic tissue produced by spheroid grafting of human adipose-derived stromal cells. Biomaterials. 2011;32:2734–47.

    Article  CAS  PubMed  Google Scholar 

  37. Rahimnejad M, Nasrollahi Boroujeni N, Jahangiri S, Rabiee N, Rabiee M, Makvandi P, et al. Prevascularized micro-/nano-sized spheroid/bead aggregates for vascular tissue engineering. Nanomicro Lett. 2021;13:182.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Piard C, Jeyaram A, Liu Y, Caccamese J, Jay SM, Chen Y, et al. 3D printed HUVECs/MSCs cocultures impact cellular interactions and angiogenesis depending on cell-cell distance. Biomaterials. 2019;222:119423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Summer S, Rossmanith E, Pasztorek M, Fiedler C, Gröger M, Rauscher S, et al. Mesenchymal stem cells support human vascular endothelial cells to form vascular sprouts in human platelet lysate-based matrices. PLoS One. 2022;17: e0278895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guo X, Zheng H, Guo Y, Heng BC, Yang Y, Yao W, et al. A three-dimensional actively spreading bone repair material based on cell spheroids can facilitate the preservation of tooth extraction sockets. Front Bioeng Biotechnol. 2023;11:1161192.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Yang C, Han B, Cao C, Yang D, Qu X, Wang X. An injectable double-network hydrogel for the co-culture of vascular endothelial cells and bone marrow mesenchymal stem cells for simultaneously enhancing vascularization and osteogenesis. J Mater Chem B. 2018;6:7811–21.

    Article  CAS  PubMed  Google Scholar 

  42. Thai VL, Candelas DO, Leach JK. Tuning the microenvironment to create functionally distinct mesenchymal stromal cell spheroids. Ann Biomed Eng. 2023;51:1558–73.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Lee J, Lee S, Kim SM, Shin H. Size-controlled human adipose-derived stem cell spheroids hybridized with single-segmented nanofibers and their effect on viability and stem cell differentiation. Biomater Res. 2021;25:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li N, Dai X, Yang F, Sun Y, Wu X, Zhou Q, et al. Spontaneous spheroids from alveolar bone-derived mesenchymal stromal cells maintain pluripotency of stem cells by regulating hypoxia-inducible factors. Biol Res. 2023;56:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C, et al. Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget. 2017;8:45200–12.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kim JY, Rhim W-K, Cha SG, Woo J, Lee JY, Park CG, et al. Bolstering the secretion and bioactivities of umbilical cord MSC-derived extracellular vesicles with 3D culture and priming in chemically defined media. Nano Converg. 2022;9:57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rovere M, Reverberi D, Arnaldi P, Palamà MEF, Gentili C. Spheroid size influences cellular senescence and angiogenic potential of mesenchymal stromal cell-derived soluble factors and extracellular vesicles. Front Bioeng Biotechnol. 2023;11:1297644.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Chiang CE, Fang YQ, Ho CT, Assunção M, Lin SJ, Wang YC, et al. Bioactive decellularized extracellular matrix derived from 3D stem cell spheroids under macromolecular crowding serves as a scaffold for tissue engineering. Adv Healthc Mater. 2021;10: e2100024.

    Article  PubMed  Google Scholar 

  49. Zeng J, Chen X, Zhang J, Qin Y, Zhang K, Li X, et al. Stem cell spheroids production for wound healing with a reversible porous hydrogel. Mater Today Adv. 2022;15:100269.

    Article  CAS  Google Scholar 

  50. Gu Y, Pigeot S, Ahrens L, Tribukait-Riemenschneider F, Sarem M, Wolf F, et al. Toward 3D bioprinting of osseous tissue of predefined shape using single-matrix cell-bioink constructs. Adv Healthc Mater. 2023;12:e2202550.

    Article  PubMed  Google Scholar 

  51. Lee J, Huh SJ, Seok JM, Lee S, Byun H, Jang GN, et al. Surface engineering of 3D-printed scaffolds with minerals and a pro-angiogenic factor for vascularized bone regeneration. Acta Biomater. 2022;140:730–44.

    Article  CAS  PubMed  Google Scholar 

  52. Zhao N, Coyne J, Abune L, Shi P, Lian XL, Zhang G, et al. Exogenous signaling molecules released from aptamer-functionalized hydrogels promote the survival of mesenchymal stem cell spheroids. ACS Appl Mater Interfaces. 2020;12:24599–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Song YC, Park GT, Moon HJ, Choi EB, Lim MJ, Yoon JW, et al. Hybrid spheroids containing mesenchymal stem cells promote therapeutic angiogenesis by increasing engraftment of co-transplanted endothelial colony-forming cells in vivo. Stem Cell Res Ther. 2023;14:193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bayaraa O, Dashnyam K, Singh RK, Mandakhbayar N, Lee JH, Park JT, et al. Nanoceria-GO-intercalated multicellular spheroids revascularize and salvage critical ischemic limbs through anti-apoptotic and pro-angiogenic functions. Biomaterials. 2023;292: 121914.

    Article  CAS  PubMed  Google Scholar 

  55. Langhans SA. Three-dimensional in vitro cell culture models in drug discovery and drug repositioning. Front Pharmacol. 2018;9:6.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Amaral RL, Miranda M, Marcato PD, Swiech K. Comparative analysis of 3D bladder tumor spheroids obtained by forced floating and hanging drop methods for drug screening. Front Physiol. 2017;8:605.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ganguli A, Mostafa A, Saavedra C, Kim Y, Le P, Faramarzi V, et al. Three-dimensional microscale hanging drop arrays with geometric control for drug screening and live tissue imaging. Sci Adv. 2021;7:eabc1323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yang M, He S, Su Z, Yang Z, Liang X, Wu Y. Thermosensitive injectable chitosan/collagen/β-glycerophosphate composite hydrogels for enhancing wound healing by encapsulating mesenchymal stem cell spheroids. ACS Omega. 2020;5:21015–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lewis NS, Lewis EE, Mullin M, Wheadon H, Dalby MJ, Berry CC. Magnetically levitated mesenchymal stem cell spheroids cultured with a collagen gel maintain phenotype and quiescence. J Tissue Eng. 2017;8:2041731417704428.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Carlsson J, Yuhas JM. Liquid-overlay culture of cellular spheroids. Recent Results Cancer Res. 1984;95:1–23.

    Article  CAS  PubMed  Google Scholar 

  61. Laschke M, Schank T, Scheuer C, Kleer S, Schuler S, Metzger W, et al. Three-dimensional spheroids of adipose-derived mesenchymal stem cells are potent initiators of blood vessel formation in porous polyurethane scaffolds. Acta Biomater. 2013;9:6876–84.

    Article  CAS  PubMed  Google Scholar 

  62. Frith JE, Thomson B, Genever PG. Dynamic three-dimensional culture methods enhance mesenchymal stem cell properties and increase therapeutic potential. Tissue Eng C Methods. 2010;16:735–49.

    Article  CAS  Google Scholar 

  63. Ingram M, Techy G, Saroufeem R, Yazan O, Narayan K, Goodwin T, et al. Three-dimensional growth patterns of various human tumor cell lines in simulated microgravity of a NASA bioreactor. In Vitro Cell Dev Biol Anim. 1997;33:459–66.

    Article  CAS  PubMed  Google Scholar 

  64. Manley P, Lelkes PI. A novel real-time system to monitor cell aggregation and trajectories in rotating wall vessel bioreactors. J Biotechnol. 2006;125:416–24.

    Article  CAS  PubMed  Google Scholar 

  65. Kato Y, Iwamoto M, Koike T, Suzuki F, Takano Y. Terminal differentiation and calcification in rabbit chondrocyte cultures grown in centrifuge tubes: regulation by transforming growth factor beta and serum factors. Proc Natl Acad Sci U S A. 1988;85:9552–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bellotti C, Duchi S, Bevilacqua A, Lucarelli E, Piccinini F. Long term morphological characterization of mesenchymal stromal cells 3D spheroids built with a rapid method based on entry-level equipment. Cytotechnology. 2016;68:2479–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bara JJ, McCarthy HE, Humphrey E, Johnson WE, Roberts S. Bone marrow-derived mesenchymal stem cells become antiangiogenic when chondrogenically or osteogenically differentiated: implications for bone and cartilage tissue engineering. Tissue Eng Part A. 2014;20:147–59.

    Article  CAS  PubMed  Google Scholar 

  68. Wilson WC Jr, Boland T. Cell and organ printing 1: protein and cell printers. The Anat Rec A Discov Mol Cell Evol Biol. 2003;272:491–6.

    Article  PubMed  Google Scholar 

  69. Ahn CB, Lee JH, Kim JH, Kim TH, Jun HS, Son KH, et al. Development of a 3D subcutaneous construct containing insulin-producing beta cells using bioprinting. Biodes Manuf. 2022;5:265–76.

    Article  CAS  Google Scholar 

  70. Heo DN, Hospodiuk M, Ozbolat IT. Synergistic interplay between human MSCs and HUVECs in 3D spheroids laden in collagen/fibrin hydrogels for bone tissue engineering. Acta Biomater. 2019;95:348–56.

    Article  CAS  PubMed  Google Scholar 

  71. Murphy KC, Hoch AI, Harvestine JN, Zhou D, Leach JK. Mesenchymal stem cell spheroids retain osteogenic phenotype through α 2 β 1 signaling. Stem Cells Transl Med. 2016;5:1229–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kuss MA, Wu S, Wang Y, Untrauer JB, Li W, Lim JY, et al. Prevascularization of 3D printed bone scaffolds by bioactive hydrogels and cell co-culture. J Biomed Mater Res B Appl Biomater. 2018;106:1788–98.

    Article  CAS  PubMed  Google Scholar 

  73. Lee J, Lee S, Ahmad T, Perikamana SKM, Lee J, Kim EM, et al. Human adipose-derived stem cell spheroids incorporating platelet-derived growth factor (PDGF) and bio-minerals for vascularized bone tissue engineering. Biomaterials. 2020;255:120192.

    Article  CAS  PubMed  Google Scholar 

  74. Karanfil AS, Louis F, Matsusaki M. Biofabrication of vascularized adipose tissues and their biomedical applications. Mater Horiz. 2023;10:1539–58.

    Article  CAS  PubMed  Google Scholar 

  75. Zhang K, Song L, Wang J, Yan S, Li G, Cui L, et al. Strategy for constructing vascularized adipose units in poly (l-glutamic acid) hydrogel porous scaffold through inducing in-situ formation of ASCs spheroids. Acta Biomater. 2017;51:246–57.

    Article  CAS  PubMed  Google Scholar 

  76. Yu SJ, Choi G, Cho Y, Lee M, Cho Y, Shin JH, et al. Three-dimensional spheroid culture on polymer-coated surface potentiate stem cell functions via enhanced cell–extracellular matrix interactions. ACS Biomater Sci Eng. 2020;6:2240–50.

    Article  CAS  PubMed  Google Scholar 

  77. Yang F, Cohen RN, Brey EM. Optimization of co-culture conditions for a human vascularized adipose tissue model. Bioengineering. 2020;7:114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Valenti MT, Dalle Carbonare L, Mottes M. Osteogenic differentiation in healthy and pathological conditions. Int J Mol Sci. 2016;18:41.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Marshall J, Barnes A, Genever P. Analysis of the intrinsic self-organising properties of mesenchymal stromal cells in three-dimensional co-culture models with endothelial cells. Bioeng. 2018;5:92.

    CAS  Google Scholar 

  80. Kronemberger GS, Dalmônico GM, Rossi AL, Leite PEC, Saraiva AM, Beatrici A, et al. Scaffold-and serum-free hypertrophic cartilage tissue engineering as an alternative approach for bone repair. Artif Organs. 2020;44:E288–99.

    Article  CAS  PubMed  Google Scholar 

  81. Côrtes I, Matsui RA, Azevedo MS, Beatrici A, Souza KL, Launay G, et al. A scaffold-and serum-free method to mimic human stable cartilage validated by secretome. Tissue Eng A. 2021;27:311–27.

    Article  Google Scholar 

  82. Laschke MW, Schank TE, Scheuer C, Kleer S, Shadmanov T, Eglin D, et al. In vitro osteogenic differentiation of adipose-derived mesenchymal stem cell spheroids impairs their in vivo vascularization capacity inside implanted porous polyurethane scaffolds. Acta Biomater. 2014;10:4226–35.

    Article  CAS  PubMed  Google Scholar 

  83. Liu X, Zhao N, Liang H, Tan B, Huang F, Hu H, et al. Bone tissue engineering scaffolds with HUVECs/hBMSCs cocultured on 3D-printed composite bioactive ceramic scaffolds promoted osteogenesis/angiogenesis. J Orthop Transl. 2022;37:152–62.

    Google Scholar 

  84. Liu X, Li L, Gaihre B, Park S, Li Y, Terzic A, et al. Scaffold-free spheroids with two-dimensional heteronano-layers (2DHNL) enabling stem cell and osteogenic factor codelivery for bone repair. ACS Nano. 2022;16:2741–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gomillion CT, Burg KJ. Stem cells and adipose tissue engineering. Biomaterials. 2006;27:6052–63.

    Article  CAS  PubMed  Google Scholar 

  86. Kim TG, Park SH, Chung HJ, Yang DY, Park TG. Hierarchically assembled mesenchymal stem cell spheroids using biomimicking nanofilaments and microstructured scaffolds for vascularized adipose tissue engineering. Adv Funct Mater. 2010;20:2303–9.

    Article  CAS  Google Scholar 

  87. Yao R, Zhang R, Lin F, Luan J. Biomimetic injectable HUVEC-adipocytes/collagen/alginate microsphere co-cultures for adipose tissue engineering. Biotechnol Bioeng. 2013;110:1430–43.

    Article  CAS  PubMed  Google Scholar 

  88. Ni R, Luo C, Ci H, Sun D, An R, Wang Z, et al. Construction of vascularized tissue-engineered breast with dual angiogenic and adipogenic micro-tissues. Mater Today Bio. 2023;18:100539.

    Article  CAS  PubMed  Google Scholar 

  89. Findlay D. Vascular pathology and osteoarthritis. Rheumatology. 2007;46:1763–8.

    Article  CAS  PubMed  Google Scholar 

  90. Favreau H, Pijnenburg L, Seitlinger J, Fioretti F, Keller L, Scipioni D, et al. Osteochondral repair combining therapeutics implant with mesenchymal stem cells spheroids. Nanomedicine. 2020;29:102253.

    Article  CAS  PubMed  Google Scholar 

  91. Mackie E, Ahmed Y, Tatarczuch L, Chen K-S, Mirams M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell biol. 2008;40:46–62.

    Article  CAS  PubMed  Google Scholar 

  92. Freeman FE, Allen AB, Stevens HY, Guldberg RE, McNamara LM. Effects of in vitro endochondral priming and pre-vascularisation of human MSC cellular aggregates in vivo. Stem Cell Res Ther. 2015;6:218.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Jang HH, Son Y, Park G, Park KS. Bone marrow-derived vasculogenic mesenchymal stem cells enhance in vitro angiogenic sprouting of human umbilical vein endothelial cells. Int J Mol Sci. 2022;24:413.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Correia C, Grayson WL, Park M, Hutton D, Zhou B, Guo XE, et al. In vitro model of vascularized bone: synergizing vascular development and osteogenesis. PLoS One. 2011;6:e28352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Costa MH, Serra J, McDevitt TC, Cabral JM, da Silva CL, Ferreira FC. Dimethyloxalylglycine, a small molecule, synergistically increases the homing and angiogenic properties of human mesenchymal stromal cells when cultured as 3D spheroids. Biotechnol J. 2021;16:2000389.

    Article  CAS  Google Scholar 

  96. Fuentes P, Torres MJ, Arancibia R, Aulestia F, Vergara M, Carrión F, et al. Dynamic culture of mesenchymal stromal/stem cell spheroids and secretion of paracrine factors. Front Bioeng Biotechnol. 2022;10:916229.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Santos RdA, Asensi KD, de Barros JHO, de Menezes RCS, Cordeiro IR, Neto JMdB, et al. Intrinsic angiogenic potential and migration capacity of human mesenchymal stromal cells derived from menstrual blood and bone marrow. Int J Mol Sci. 2020;21:9563.

  98. Place TL, Domann FE, Case AJ. Limitations of oxygen delivery to cells in culture: an underappreciated problem in basic and translational research. Free Radic Biol Med. 2017;113:311–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sano K, Usui M, Moritani Y, Nakazawa K, Hanatani T, Kondo H, et al. Co-cultured spheroids of human periodontal ligament mesenchymal stem cells and vascular endothelial cells enhance periodontal tissue regeneration. Regen Ther. 2020;14:59–71.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ministry of Science and ICT of Korea (NRF-2021R1C1C2004576, RS-2023-00222737, NRF-2022R1I1A1A01072365 and NRF- 2022R1C1C1008610). This research was also supported by the Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korean government (the Ministry of Science and ICT, the Ministry of Health & Welfare). (Code: KFRM 22A0105L1-11).

Author information

Authors and Affiliations

  1. Department of IT Convergence (Brain Korea Plus 21), Korea National University of Transportation, Chungju, 27469, Republic of Korea

    Yoonjoo Kang & Hwan D. Kim

  2. Department of Polymer Science and Engineering, Korea National University of Transportation, 50 Daehak-ro, Chungju, 27469, Republic of Korea

    Jinwoo Na, Gul Karima & Hwan D. Kim

  3. School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea

    Sivashanmugam Amirthalingam & Nathaniel S. Hwang

  4. Institute of Engineering Research, Seoul National University, Seoul, 08826, Republic of Korea

    Sivashanmugam Amirthalingam & Nathaniel S. Hwang

  5. Department of Biomedical Engineering, Korea National University of Transportation, Chungju, 27469, Republic of Korea

    Hwan D. Kim

Authors
  1. Yoonjoo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinwoo Na
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gul Karima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sivashanmugam Amirthalingam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nathaniel S. Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hwan D. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hwan D. Kim.

Ethics declarations

Conflict of interest

The author declares no conflict of interest.

Ethical statement

There are no animal experiments carried out for this article.

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

Kang, Y., Na, J., Karima, G. et al. Mesenchymal Stem Cell Spheroids: A Promising Tool for Vascularized Tissue Regeneration. Tissue Eng Regen Med (2024). https://doi.org/10.1007/s13770-024-00636-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13770-024-00636-2

Keywords

Search

Navigation