UCLA researchers in the Department of Bioengineering have developed a method to boost extracellular vesicles' (EVs) production and potency, potentially allowing large-scale clinical-grade EV manufacture for immunomodulatory therapeutics.
BACKGROUND
Extracellular vesicles (EVs) are one of the most important mediators of cell-to-cell communication. EVs regulate a diverse range of biological processes, including immunomodulation and regeneration, thus representing potential therapeutic agents in these pathological areas. While EV-based therapeutics have been developing exponentially over the past few years, EVs' clinical use for immunomodulation is currently limited. Among the significant issues to be resolved is the inconsistent and unstable source of immunomodulatory EVs, namely, mesenchymal stem cells (MSCs). Due to the lack of universal MSC culture protocols, current MSC-derived EVs bear a significant variability between batches. MSCs also have a limited lifespan and a tremendous donor-to-donor variability, further hindering a uniform population mass-production. Therefore, a new method of EV production, with better reproducibility and scalability, is in urgent need to meet the industrial standard and advance the EV-based therapeutics to the next level: clinical use.
INNOVATION
UCLA researchers in the Department of Bioengineering have developed a method to boost EVs' production and potency. Researchers utilized the induced pluripotent stem cells (iPSCs) as an alternative source to overcome the limitation of the MSC-derived EVs. Unlike MSCs, iPSCs have defined culture conditions and protocols, which can eliminate the batch-to-batch variability. Researchers found that the iPSC-derived EVs maintained the same look and size as the MSC-EVs while demonstrating superior immunomodulatory properties compared to the MSC counterparts. Specifically, the iPSC-EVs increase the formation of regulatory T cells from both primary human and mouse T cells and augment the production of anti-inflammatory cytokines. Also, researchers found that mechanical stimulation of cells in a bioreactor could significantly increase EV production. This method can be applied to both MSCs and iPSCs and resulted in substantially more EV production, up to 18-fold, compared to the traditional static culture. This method did not induce changes in other properties of the EV product, such as size. Therefore, deriving EVs from iPSCs cultured in a bioreactor is a potential method for achieving large-scale clinical-grade EV manufacturing for immunomodulatory therapeutics.
POTENTIAL APPLICATIONS
• Industrial production of immunomodulatory EVs
• Supports tissue regeneration
• Decreases the risk of transplant rejection
ADVANTAGES
• Easily expandable; 18-fold increase in EV production when mechanical stimulation is applied
• Highly reproducible; iPSCshave established culture conditions and protocols
• Superior immunomodulation capability
• More immunocompatible EVs could be produced if genetically modified iPSCs are used
DEVELOPMENT TO DATE
The producibility and quality of the method have been assessed. iPS-EVs decreased batch-to-batch variability and increased immunomodulatory capabilities. Applying mechanical force by culturing cells in a bioreactor boosted EV production up to 18-fold.
RELATED PAPERS
Nature Review Drug Discovery 2013, Apr, 12;5 (https://www.nature.com/articles/nrd3978)
Cell Stem Cell 2019, Apr, 24;4 (https://doi.org/10.1016/j.stem.2019.02.005)