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Article

Extracellular Vesicle Secretion from 3D Culture of Human Adipose-Derived Mesenchymal Stem Cells in Scalable Bioreactors

1
Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, 2525 Pottsdamer St., Tallahassee, FL 32310, USA
2
Division of Biology and Medicine, Brown University, 69 Brown St., Providence, RI 02912, USA
3
Lawton Chiles High School, 7200 Lawton Chiles Ln, Tallahassee, FL 32312, USA
*
Authors to whom correspondence should be addressed.
These two authors contributed equally to this work.
Current address: Pratt School of Engineering, Duke University, 2138 Campus Drive, Durham, NC 27708, USA.
§
Current address: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, 1304 W Green St., Urbana, IL 61801, USA.
Bioengineering 2025, 12(9), 933; https://doi.org/10.3390/bioengineering12090933 (registering DOI)
Submission received: 31 July 2025 / Revised: 22 August 2025 / Accepted: 26 August 2025 / Published: 29 August 2025

Abstract

Human mesenchymal stem cells (hMSCs) and their secreted extracellular vesicles (EVs) are promising therapeutics to treat degenerative or inflammatory diseases such as ischemic stroke and Alzheimer’s disease (AD). hMSC-EVs have the coveted ability to contain therapeutically relevant biomaterials; however, EV biogenesis is sensitive to the culture microenvironment in vitro. Recently, the demand for hMSC-EVs has increased dramatically, highlighting the need for scalable bioreactors for large-scale biomanufacturing. In this study, adipose-derived hMSCs were seeded in 2D plates, an ultralow-attachment (ULA) plates as static aggregates, a novel vertical wheel bioreactor (VWBR) as aggregates, and a spinner flask bioreactor (SFB). EV secretion was quantified and compared using ExtraPEG-based ultracentrifugation and nanoparticle tracking analysis. Compared to the 2D group, significantly higher total EV production and cell productivity in the bioreactors were observed, as well as the upregulation of EV biogenesis genes. Furthermore, there was increased EV production in the VWBR compared to the SFB and the static ULA control. Functional assessments demonstrated that EVs, when delivered via culture medium or hydrogel-based systems, significantly attenuated oxidative stress elevation, suppressed proinflammatory cytokine secretion (e.g., TNF-α) and gene expression, and inhibited nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) activation and neurodegenerative markers across in vitro assays. These findings suggest EV-mediated mitigation of oxidative and inflammatory pathways, potentially through modulation of the NF-κB signaling cascade. This study shows the influence of bioreactor types and their microenvironments on EV secretion in hMSCs and their applications in hMSC-EV production and bioengineering.
Keywords: human mesenchymal stem cells; aggregates; vertical wheel bioreactor; extracellular vesicles; biogenesis; neural degeneration human mesenchymal stem cells; aggregates; vertical wheel bioreactor; extracellular vesicles; biogenesis; neural degeneration

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MDPI and ACS Style

Ma, S.; Ene, J.; McGarraugh, C.; Ma, S.; Esmonde, C.; Liu, Y.; Li, Y. Extracellular Vesicle Secretion from 3D Culture of Human Adipose-Derived Mesenchymal Stem Cells in Scalable Bioreactors. Bioengineering 2025, 12, 933. https://doi.org/10.3390/bioengineering12090933

AMA Style

Ma S, Ene J, McGarraugh C, Ma S, Esmonde C, Liu Y, Li Y. Extracellular Vesicle Secretion from 3D Culture of Human Adipose-Derived Mesenchymal Stem Cells in Scalable Bioreactors. Bioengineering. 2025; 12(9):933. https://doi.org/10.3390/bioengineering12090933

Chicago/Turabian Style

Ma, Shaoyang, Justice Ene, Colton McGarraugh, Shaoxuan Ma, Colin Esmonde, Yuan Liu, and Yan Li. 2025. "Extracellular Vesicle Secretion from 3D Culture of Human Adipose-Derived Mesenchymal Stem Cells in Scalable Bioreactors" Bioengineering 12, no. 9: 933. https://doi.org/10.3390/bioengineering12090933

APA Style

Ma, S., Ene, J., McGarraugh, C., Ma, S., Esmonde, C., Liu, Y., & Li, Y. (2025). Extracellular Vesicle Secretion from 3D Culture of Human Adipose-Derived Mesenchymal Stem Cells in Scalable Bioreactors. Bioengineering, 12(9), 933. https://doi.org/10.3390/bioengineering12090933

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