Mesenchymal Stem Cell–derived Exosomes: Are They Another Therapeutic Method for Extracorporeal Membrane Oxygenation–supported Acute Respiratory Distress Syndrome?

To the Editor:

We read the article by Millar and colleagues with great interest (1). They illustrated that even though induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (MSCs) reduced lung injury and inflammation, they impaired the membrane oxygenator and did not ameliorate oxygenation in a sheep model of acute respiratory distress syndrome (ARDS) and extracorporeal membrane oxygenation (ECMO). Based on the therapeutic promise of MSCs, it is important to explore the effect of MSCs in a preclinical model of ECMO-supported ARDS.

The result reported impaired membrane oxygenator and increased transmembrane pressure caused by iPSC-derived MSCs, coinciding with the results of their other ex vivo model of ARDS and ECMO. It reported that the intravascular delivery of MSCs also led to declined function of the membrane oxygenator and increased transmembrane pressure gradient at 4 hours (2). It is obvious that these results demonstrated that the delivery of MSCs by intratracheal or intravenous method was not beneficial for oxygenation and the membrane oxygenator. In addition, the results showed iPSC-derived MSCs led to pulmonary arterial thrombosis. This result might be associated with the instability of iPSC-MSCs and the changed cell function by altered microenvironment after cell adhesion to the oxygenator. It is worth discussing the solution for these results. Early clinical trials of MSCs excluded the patients with ARDS supported by ECMO. Could we have another method to apply MSCs in patients with ARDS with ECMO?

ARDS is caused by multiple reasons, such as severe infection (including the current epidemic coronavirus disease [COVID-19)], trauma, or shock. The mortality of severe ARDS was even over 40% (3). Although multiple studies have been conducted on mechanisms and therapy, the effective treatment for ARDS is still uncertain, especially for severely ill patients. The disorder is characterized by dyspnea, refractory hypoxemia, and diffused alveolar injury, and severely ill patients are also in a hyperinflammatory state. It is difficult to manage the complicated state. Therefore, the application of MSCs in severe ARDS supported by ECMO is a chance to improve the survival rate.

The authors provided a profound discussion on the possible reasons. However, given the adhesion and cell size of MSCs and the little efficacy of MSCs on an ECMO-supported ARDS model as reported in existing studies, we think it may be not be proper to deliver the cells to ECMO-supported patients directly. The therapeutic effects of MSCs are largely attributed to their paracrine effects. Exosomes (exos) are considered to be the critical products of MSC efficacy. They are one kind of extracellular vesicles. MSCs have immunomodulatory and antiinfection effects that have possessed therapeutic prospects in various preclinical models. The exos from MSCs also have these effects. It has been reported that MSC-derived exos (MSC-exos) could restore oxygenation and alleviate cytokine storm in patients with moderate to severe ARDS caused by COVID-19 (4). Accumulating studies have found the potential role of MSC-exos in preclinical models of ARDS (5). As a result, compared with MSCs in ECMO, the advantages of MSC-exos are pretty significant. First, MSC-exos are secreted by MSCs actively in vitro, packaging effective biological molecules from MSCs such as KGF (keratinocyte growth factor) and Ang-1 (angiopoietin-1). Furthermore, exos are more stable and have lower immunogenicity than MSCs. Even if the microenvironment changed, the effect of MSC-exos will not be altered. Therefore, they may not have the same procoagulant effects as transplanted MSCs have in an ECMO circuit. Second, the diameter of MSC-exos is 30–100 nm, which is much smaller than the diameter of MSCs and pores in the membrane oxygenator. This may potentially avoid adhesion to the oxygenator to impair it. Thus, the application of MSC-exos may contribute to oxygenation. Third, MSCs are activated or primed by an abnormal microenvironment, which can be made in vitro. MSCs in the desired microenvironments will produce more ideal exos, such as stronger antiinflammatory MSC-exos (6).

It is expected that MSC-exos can be considered in the ECMO-supported ARDS model as a next step.