Extracellular Vesicles: A New Avenue of Mesenchymal Stem Cell Therapies in Transplant Medicine

Mesenchymal stem cells (MSCs) are multipotent nonhematopoietic cells with therapeutic potential due to their immunomodulatory and self-renewing capacity. Extensive studies have described the fundamental biology of these cells that make them attractive for use in the treatment of an array of diseases and have led to an explosion of active clinical trials to define clinical use cases [1]. However, some recent evidence has dampened excitement surrounding the use of MSCs in clinical practice. Among other limitations, MSCs are difficult to store and distribute; they are not fully immune privileged posing a risk of immune response; they can cause ischemia due to microvascular occlusion; and they carry a theoretical risk of tumorigenesis due to unrestricted replication [2].

The clinical setting has seen some recent high-profile unsuccessful trials (eg, NCT04075825, in which adipose-derived MSCs were injected locally in patients with Crohn's fistulas) that is prompting reverse-translation efforts to understand the importance of factors such as MSC parent cell tissue source and donor characteristics [3].

The treatment of solid organ transplant rejection was defined early on as a potential major indication for MSC therapy due to the cells' immunomodulatory properties [4] and several ongoing studies are investigating the ability of these cells to reduce the need for immunosuppression or treat complications such as rejection and graft-versus-host disease (GVHD) (eg, NCT03478215). In parallel, recent work has progressed quickly in defining the clinical potential of MSC-derived extracellular vesicles (EVs) in transplant patients due to the limitations of the parent cells [5].

Here, Lightner and colleagues report on the clinical use of EVs in seven patients who had undergone liver and/or intestinal transplant and were suffering from GVHD or graft rejection [6]. Although the number of patients treated was small in this series, the observed clinical effects were remarkable, with all patients demonstrating clinical and histological improvement. Importantly, no serious side effects were observed in any of the patients, which is significant given the high baseline degree of immunosuppression used after bowel transplantation.

Further studies are needed to better understand the therapeutic potential of EVs in patients who experience complications after solid organ transplant. These two studies highlight the possibility that EV therapy may transform post-transplant medical care, particularly when it comes to rejection and GVHD that drive the majority of graft failure [7]. An important area of research will be in understanding the relative efficacy of EVs compared with parent MSCs although these trials will be difficult to conduct in a head-to-head manner and preclinical models are yielding important insights [8].

Lightner and colleagues point out that future clinical trials will also need to be designed carefully to understand the efficacy of EVs compared with other conventional immunosuppression that is used in these patients, particularly as institutional protocols vary widely among transplant centers.

EVs have clear benefits over their parent MSCs, but they also have important drawbacks. Perhaps the most critical of these is their nonreplicative quality, which will naturally limit tissue occupancy. This raises the question of how to optimally deliver EVs to the target tissue to maximize their immunomodulatory and regenerative potential. Multiple studies are investigating directed administration of MSCs to target tissues, with some even looking at super-selective targeting using the tissue's arterial supply (eg, NCT04312113 and NCT01224327). In the intestine, this approach has been used to deliver steroids in patients with inflammatory bowel disease and GVHD, even in children (NCT05587673) [9].

There are currently no ongoing clinical trials investigating this approach for EVs, but animal biodistribution studies suggest that few EVs (or MSCs) reach the intestine after intravenous administration [10]. Whether the clinical response observed by Lightner and colleagues resulted from only a few EVs or whether paracrine effects could be at play is unclear and should be addressed in future clinical studies to develop robust treatment protocols.

In summary, Lightner and colleagues report a remarkable clinical response in a series of patients with rejection and/or GVHD after solid organ transplant who were treated with EVs. This therapy has tremendous potential for addressing leading causes of graft failure, and this study represents an important step toward bringing MSC-derived therapies to patients.