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

From the Authors:

We thank Zhang and Hei for their insightful comments on our study of mesenchymal stromal cells (MSCs) in a sheep model of extracorporeal membrane oxygenation and acute respiratory distress syndrome (ARDS) (1). Their principal thesis is that the adverse interaction that we observed, between MSCs and the membrane oxygenator, may be overcome by substituting MSCs with MSC-derived exosomes. This proposal has merit. The MSC secretome has been of interest as a therapeutic for some time, particularly MSC-derived extracellular vesicles (2), MSC-derived exosomes (3), and MSC-conditioned media (4). These each offer several theoretical advantages over conventional MSC therapy. First, contents of the secretome do not express major histocompatibility complex antigens, removing concerns about immunogenicity. Second, components of the secretome are, in general, easier to store and less susceptible to the adverse effects of storage on efficacy. Third, components of the MSC secretome are much smaller than the cells from which they are derived and thus less likely to be subject to “trapping” in the pulmonary circulation (5). Recently, an early phase trial of an MSC-derived exosome treatment for severe coronavirus disease (COVID-19) has been reported with no apparent safety issues (6). However, there are some unresolved issues that should be borne in mind.

Paracrine actions are the principle means by which MSCs exert benefit in ARDS, although several alternative mechanisms have been described, such as mitochondrial transfer from MSCs to damaged alveolar epithelial cells (7). The inability of secretome-based therapies to reproduce these actions may limit their efficacy (8, 9). The translation of MSC secretome–based therapies is also limited by challenges in scaling manufacturing for clinical purposes, an issue that is overcome by the use of induced pluripotent cell–derived MSCs, like those used in our study (1). With specific regard to our study, the observation that pulmonary emboli were more frequent in the induced pluripotent cell–derived MSC group may not be uniquely associated with the use of a cell-based therapy. A variety of preclinical studies have described the procoagulant activity of MSC-derived extracellular vesicles (10, 11).

Despite these caveats, Zhang and Hei’s point is well made and highlights the work that is still required to successfully advance cell therapy for ARDS, especially in the context of extracorporeal organ support. We hope that our study illustrates the usefulness of clinically relevant, high-fidelity animal models in advancing these efforts.