In brief

Mesenchymal stem cell exosome therapy, currently in clinical trials to treat severe COVID-19, inhibits neutrophil and complement activation via CD59.

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Tiny packages bring (cytokine) storm relief

16 Feb 2023

A*STAR scientists decipher how a stem cell-based treatment stops the uncontrolled inflammation associated with severe COVID-19 cases.

Tropical storms form through a confluence of factors: sunlight warms humid ocean air, which strong winds whirl up to cooler altitudes, condensing the moisture into massive clouds that bring down torrential rainfall.

Likewise, COVID-19 can at times trigger a storm of its own: some infections set off an exaggerated immune response known as a cytokine storm, where a cocktail of inflammatory molecules with potentially deadly consequences floods the body.

Clinical solutions to calm this cytokine storm in critically ill COVID-19 patients are limited and mostly address its symptoms, but not its root cause. Sai Kiang Lim, Research Director at A*STAR’s Institute of Molecular and Cell Biology (IMCB), discovered and continues to study the mesenchymal stem cell (MSC) exosomes currently in clinical trials for the treatment of severe COVID-19.

MSC exosomes are nanosized, membrane-bound packets of bioactive proteins and growth factors that have been shown to moderate overactive immune systems. However, how exactly exosomes work in the context of COVID-19 has remained unclear.

Lim’s group had previously discovered that exosomes could dampen immune activity in a skin condition called psoriasis by moderating how neutrophils secrete two immune factors: cytokines and complement proteins. Interestingly, both factors have also been implicated as activators of COVID-19 cytokine storms.

“We postulated that exosomes could potentially modulate the dual problem of complements and neutrophils in severe COVID-19,” said Lim.

In collaboration with Kong-Peng Lam, Executive Director of A*STAR’s Singapore Immunology Network (SIgN), the team simulated infections in blood samples from healthy donors. They found that complements, activated by infection, caused neutrophils in the samples to release neutrophil extracellular traps (NETs)—threads of DNA and antimicrobial proteins—and interleukin-17 (IL-17), a proinflammatory cytokine.

Adding MSC exosomes to the mix, however, put the brakes on this inflammatory cascade. The researchers found that a membrane protein on exosomes called CD59 blocked complement activation, NET formation and IL-17 release, providing valuable evidence on how exosome therapy might treat vulnerable COVID-19 patients.

Despite their potential, the development of MSC exosomes as an approved drug will require further R&D to overcome the technical and regulatory challenges of reproducing them on a large scale. Still, Lim is optimistic that the exosome research community will rise to meet these challenges.

“There are many hurdles, but the MSC exosome community around the world is working together to address them,” she said, adding that the Singapore-based Society for Clinical Research and Translation of Extracellular Vesicles Singapore (SOCRATES) is leading global efforts to bring exosome therapies to patients.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB), the Singapore Immunology Network (SIgN) and the Bioprocessing Technology Institute (BTI).

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Loh, J.T., Zhang, B., Teo, J.K.H., Lai, R.C., Choo, A.B.H., et al. Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes. Cytotherapy  24, 711 – 719 (2022) | article

About the Researchers

Sai-Kiang Lim received her PhD degree from SUNY, Buffalo, in 1992, before completing her postdoctoral training at Columbia University first as a Cooley’s Anemia Foundation Research Fellow (1992-94) and then a Leukemia Society of America Special Fellow (1994-96). She has since led independent research groups at the National University Medical Institute, the National University of Singapore (1996-2001), the A*STAR Genome Institute of Singapore (2002-2007) and the A*STAR Institute of Medical Biology (2007-2020). Lim is currently a Principal Investigator at the A*STAR Institute of Molecular & Cell Biology, with major research interests in natural and synthetic nano lipid vesicles with specific focus on their synthesis and purification, biochemical and biophysical characterisation, and diagnostic and therapeutic applications.
Kong-Peng Lam obtained his PhD in Immunology in 1994 from the College of Physicians & Surgeons at Columbia University, US. He then carried out postdoctoral research at the Institute for Genetics, University of Cologne, working to understand B cell biology and development. He is currently the Executive Director of A*STAR’s Singapore Immunology Network (SIgN), a Professor in the Departments of Microbiology and Immunology, Physiology, and Pediatrics at Yong Loo Lin School of Medicine, National University of Singapore (NUS), and an Adjunct Professor in the School of Biological Sciences at Nanyang Technological University (NTU).

This article was made for A*STAR Research by Wildtype Media Group