Optimizing cell therapy by sorting cells with high extracellular vesicle secretion

In regenerative medicine, extracellular vesicles (EVs) have shown great promise as therapeutic agents. EVs are tiny particles released by cells that carry a variety of bioactive molecules, playing key roles in communication between cells and promoting healing and regeneration. However, one of the critical challenges in harnessing EVs for clinical therapies has been finding an efficient way to select and enrich cells that produce high levels of these beneficial vesicles.

The Challenge

Current methods for selecting therapeutic cells typically rely on surface markers. These markers, however, do not correlate well with the cells’ ability to secrete EVs or their therapeutic potential. As a result, it’s been difficult to ensure that the chosen cells are the most effective for treatment.

Introducing Nanovial Technology

Researchers at UCLA have now developed an innovative solution using nanovial technology. This cutting-edge approach allows for the enrichment of millions of individual cells based on their EV secretion capabilities. Essentially, nanovials are tiny containers that can capture and hold individual cells. By analyzing these cells, scientists can identify and select those that produce the most EVs.

Overview of isolation and downstream analysis of cells based on the amount of EV secretion

Fig. 1

A Cells are loaded in nanovials (blue) that are conjugated with anti-CD63 capture antibodies and allowed to secrete EVs. B Secreted EVs from each cell are captured by the surrounding nanovial and labeled with a fluorescent antibody against CD9 on the surface of EVs. C Nanovials and corresponding single cells are sorted based on the level of fluorescence signal associated with the captured EVs (High vs. Low Secretors) using a standard cell sorter. D Downstream transcriptomic analysis is performed on the High or Low-secretor cells to characterize gene expression differences. In vivo studies are performed with cells expanded from High Secretor or Low-Secretor populations to characterize the effect on therapeutic outcome. AB, and D created with BioRender.com, and released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.

Application to Mesenchymal Stem Cells

The study focused on mesenchymal stem cells (MSCs), a type of stem cell known for their regenerative properties. Using the nanovial technology, the researchers were able to identify MSCs with high levels of EV secretion. These selected MSCs not only maintained their high EV production after being sorted and regrown but also showed unique transcriptional profiles. These profiles were associated with processes involved in EV biogenesis (the formation of EVs) and vascular regeneration (the repair and formation of blood vessels).

Improved Heart Function in Mice

To test the therapeutic potential of these high-EV-secreting MSCs, the researchers used a mouse model of myocardial infarction, commonly known as a heart attack. The results were promising: mice treated with the high-secreting MSCs showed significant improvements in heart function compared to those treated with MSCs that produced fewer EVs.

Implications for Regenerative Medicine

This breakthrough highlights the crucial role of EV secretion in regenerative therapies. By selecting cells based on their EV production, it is possible to enhance the therapeutic efficacy of treatments. This approach could revolutionize the way regenerative therapies are developed and applied, potentially leading to better outcomes for patients suffering from various conditions, including heart disease.


The development of nanovial technology for enriching cells based on EV secretion represents a significant advancement in regenerative medicine. By ensuring that the most effective cells are used in therapies, we can improve treatment outcomes and offer new hope for patients with conditions that currently have limited treatment options. As this technology continues to evolve, it may pave the way for more precise and effective regenerative therapies in the future.

Koo D, Cheng X, Udani S, Baghdasarian S, Zhu D, Li J, Hall B, Tsubamoto N, Hu S, Ko J, Cheng K, Di Carlo D. (2024) Optimizing cell therapy by sorting cells with high extracellular vesicle secretion. Nat Commun 15(1):4870. [article]

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