Coronavirus is Here! Could Exosomes Help?

Coronavirus is here – at this point more than 100,000 people have tested positive for this viral infection, and more than 5,000 people have died. Many of you already know this, but for those that haven’t heard about coronavirus yet, stay wherever you are, and avoid infection with this virus. Everyone else that may be at risk for exposure should follow the recommendations for prevention including social distancing, frequent hand washing and avoiding crowded places. That being said, even the best preventive measures cannot guarantee that you won’t be exposed to this virus, which can survive for 10 days on surfaces. 

Clinical researchers are rapidly trying to develop vaccines and treatment for this virus, which causes pneumonia and potentially fatal complications in the elderly and infirm. One clinical effort underway in China, where the virus originated has successfully used umbilical cord-derived stem cells to substantially improve the course of this infection. Knowing that these stem cells exert their biological effects by releasing exosomes, it might be reasonable to consider the use of stem cell exosomes, which are much more abundant and readily available than stem cells, on the basis of compassionate use and in an attempt to reduce the mortality rate of this disease.

Coronavirus infection primarily effects the lungs causing pneumonia, acute lung injury and potentially acute respiratory distress syndrome (ARDS), which can cause respiratory failure. There is no effective pharmacotherapy for ARDS, and treatment generally consists of respiratory support. There are clinical trials using mesenchymal stem cells (MSCs) for the treatment of acute lung injury underway,, and these have shown promising early results, however limited supply, difficulty with storage and distribution, and risk of iatrogenic disease limit the potential of this type of therapy. 

MSC exosomes have also been investigated in preclinical studies as an acellular alternative to cell-based therapy for ARDS. MSC exosomes have been shown to reduce the levels of pro-inflammatory signaling molecules, which contribute to the pathogenesis of ARDS. They also increase the levels of anti-inflammatory signaling mediators that may help to reduce the severity of the lung injury, which causes increased permeability of the alveolar epithelium. The resulting accumulation of proteinaceous fluid in the smallest air sacs of the lungs impairs the normal oxygen exchange between the lungs and the circulation. Other contents of MSC exosomes, such as keratinocyte growth factor, may help to restore the normal barrier of the alveolar epithelium and contribute to the clearance of the fluid in the alveoli. MSC exosomes have also demonstrated the ability to transfer mitochondria to cells, potentially contributing to their ability to maintain cellular energy metabolism and increasing cellular survival. These and other effects of MSC exosomes demonstrated in preclinical studies of ARDS suggest the potential of exosomes as a therapeutic agent.

Beyond their effects in preclinical models of ARDS, MSC exosomes may also interfere directly with viral replication to reduce the levels of the virus. In vitro studies of both influenza and hepatitis C virus (HCV) have demonstrated the ability of MSC exosomes to inhibit viral replication via transfer of micro RNA (miRNA). Both of these viruses are RNA viruses, like coronavirus, and the pathogenesis of the pulmonary disease in influenza is not dissimilar to that of coronavirus. In a pig model of influenza virus, intratracheal administration of MSC-EVs 12 h after influenza virus infection significantly reduced virus shedding in the nasal swabs, influenza virus replication in the lungs, and virus-induced production of proinflammatory cytokines in the lungs of influenza-infected pigs. In the study of HCV infection, researchers were able to identify four specific miRNA molecules (let-7f, miR-145, miR-199a, and miR-221) that mediated RNA-induced silencing complexes to inhibit viral RNA translation to protein and reduce viral replication. Bioinformatic analysis of the RNA genome of these viruses and comparison with the miRNA contents of the exosomes enabled researchers to not only detect potential direct anti-viral activity of the exosomes, but also identified the specific miRNA molecules involved and their mechanism of action. The same type of analysis could be done using the RNA genome of coronavirus.

The positive preclinical studies on MSC exosomes as a therapy for ARDS and their inhibitory activity on similar viruses may warrant expedited investigation of MSC exosomes as a readily available therapy for coronavirus infection. The next steps may involve in vitro studies of the effects of MSC exosomes on lung epithelial cells incubated with coronavirus. Rapid investigation of these naturally occurring stem cell exosomes may help to reduce the morbidity and mortality of this pandemic virus.