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Specificity of 3D MSC Spheroids Microenvironment: Impact on MSC Behavior and Properties

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Abstract

Mesenchymal stem cells (MSC) have been considered the promising candidates for the regenerative and personalized medicine due to their self-renewal potential, multilineage differentiation and immunomodulatory capacity. Although these properties have encouraged profound MSC studies in recent years, the majority of research has been based on standard 2D culture utilization. The opportunity to resemble in vivo characteristics of cells native niche has been provided by implementation of 3D culturing models such as MSC spheroid formation assesed through cells self-assembling. In this review, we address the current literature on physical and biochemical features of 3D MSC spheroid microenvironment and their impact on MSC properties and behaviors. Starting with the reduction in the cells’ dimensions and volume due to the changes in adhesion molecules expression and cytoskeletal proteins rearrangement resembling native conditions, through the microenvironment shifts in oxygen, nutrients and metabolites gradients and demands, we focus on distinctive and beneficial features of MSC in spheroids compared to cells cultured in 2D conditions. By summarizing the data for 3D MSC spheroids regarding cell survival, pluripotency, differentiation, immunomodulatory activities and potential to affect tumor cells growth we highlighted advantages and perspectives of MSC spheroids use in regenerative medicine. Further detailed analyses are needed to deepen our understanding of mechanisms responsible for modified MSC behavior in spheroids and to set future directions for MSC clinical application.

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Acknowledgements

We thank prof. T. Brevini for critical reading the manuscript and valuable remarks for its improving.

Funding

This work was supported by COST (European Cooperation in Science and Technology) Action CA16119 CellFit (http://cost-cellfit.eu/). The work was also supported by the Ministry of Education, Science and Technological Development, Republic of Serbia (contract number 451–03-68/2020–14/200015), Bulgarian National Science Fund, Sofia, Bulgaria, DCOST01/18 and KP-06COST/21, Ministry of Education, Youth and Sports of the Czech Republic (Grant number LTC-18059).

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Authors and Affiliations

  1. Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Dr. Subotića 4, PO BOX 102, Belgrade, 11129, Serbia

    Aleksandra Jauković, Drenka Trivanović & Tamara Kukolj

  2. Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, 73 Tzarigradsko shoes, 1113, Sofia, Bulgaria

    Desislava Abadjieva, Elena Stoyanova, Milena Kostadinova, Shina Pashova, Snejana Kestendjieva, Elena Kistanova & Milena Mourdjeva

  3. IZKF Group Tissue Regeneration in Musculoskeletal Diseases, University Clinics, Röntgenring 11, D-97070, Wuerzburg, Germany

    Drenka Trivanović

  4. Bernhard-Heine-Center for Locomotion Research, University Wuerzburg, Wuerzburg, Germany

    Drenka Trivanović

  5. Department of Obstetrics and Gynecology, University Hospital and Masaryk University, Obilní trh 11, 602 00, Brno, Czech Republic

    Michal Jeseta

  6. Department of Veterinary Sciences, Czech University of Life Sciences in Prague, Kamýcká 129, 165 00, Suchdol, Praha 6, Czech Republic

    Michal Jeseta

Authors
  1. Aleksandra Jauković
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  2. Desislava Abadjieva
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  4. Elena Stoyanova
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  7. Snejana Kestendjieva
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  8. Tamara Kukolj
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  9. Michal Jeseta
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  10. Elena Kistanova
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  11. Milena Mourdjeva
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Contributions

MM, AJ and EK gave the idea, created the conception of the work, interpreted the data and drafted the main version; MJ revised and made contribution to the conception. All performed the literature search and contributed to writing the specific parts of review as follow: AJ,DT,TK - 2.2, 2.3, 3; DA -4; EK -4,6, Table 2; ES-1, 2.1, 6, Table 1; MK-5.4; SP-5.3; SK- 5.1,5.2; MJ- Intr. and Conc., MM-2.1, 5.4, 6, Fig. 2, AJ, TK – Fig. 1. All also approved the final version for publication.

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Correspondence to Milena Mourdjeva.

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Jauković, A., Abadjieva, D., Trivanović, D. et al. Specificity of 3D MSC Spheroids Microenvironment: Impact on MSC Behavior and Properties. Stem Cell Rev and Rep 16, 853–875 (2020). https://doi.org/10.1007/s12015-020-10006-9

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