Organ Repair and Regeneration During Ex Situ Dynamic Preservation: The Future is Nano

Abstract

Organ preservation and assessment with machine perfusion (MP) has provided transplant physicians with the ability to evaluate and select grafts suitable for transplantation. Nevertheless, the discard of organs considered too damaged still sustains the imbalance between donor organs supply and demands. Therefore, there is the pressing clinical need for strategies to repair and/or regenerate organs before transplantation, and MP is uniquely positioned to satisfy this need. The systemic administration of mesenchymal stromal cells (MSC) was shown to reduce ischemia-reperfusion injury in pre-clinical organ transplant models but could not be reproduced in clinical transplantation, largely because of inefficient cell delivery. The administration of MSC during MP is one strategy that recently gained much attention as an alternative delivery method to target MSC directly to the donor organ. However, careful reinterpretation of preliminary results reveals that this approach is equally limited by a suboptimal delivery of short-lived MSC to the target organ. In contrast, the use of MSC secretome and/or extracellular vesicles therapy during MP seems to be more efficient in harnessing MSC properties during MP. In this mini review we speculate on the future of the novel niche of ex situ organ repair and regeneration before transplantation.

Keywords: dynamic preservation; extracellular vesicles; machine perfusion; mesenchymal stromal cell; organ preservation; organ regeneration; organ repair.

FIGURE 1

Overview of current knowledge on cell therapy delivery during ex situ dynamic preservation. Mesenchymal stromal cells (MSC) are perfect candidates for organ repair and regeneration during ex situ dynamic organ preservation due to their anti-inflammatory, regenerative, and immunomodulatory properties. However, a “device barrier” created by components of the perfusion circuit (i.e., oxygenator(s) and filter(s)) sequester the cells from the circulating perfusate, with a bottleneck effect on the number of cells that effectively reach the parenchyma during perfusion. Additionally, migration of stem cells out of the vascular space is infrequent, only few cells are usually observed in the parenchymal space at histology, and parenchymal retention rate of stem cell is rather low. Furthermore, monocytes may actively eliminate successfully engrafted stem cells, similarly to what has been previously observed in pre-clinical studies. Because secretion of soluble factors has been observed during perfusion, it is plausible that the biological effects of stem cells are mostly dependent on paracrine mediators, extracellular vesicles (EV) included. EV delivery during ex situ dynamic organ preservation has been shown to circumvent the “device barrier” while intracellular uptake of EV has been demonstrated during lung and liver perfusion specifically, resulting in significant anti-inflammatory and regenerative effects. Therefore, EV therapy may be more effective than MSC therapy in promoting organ repair and regeneration during ex situ dynamic organ preservation because of more efficient therapy delivery. Next to a more efficient therapy delivery, cell-free therapy with EV prevents resident monocytes activation and eliminates the risk of malignant transformation and recipient sensitization, which cannot be excluded when allogenic stem cells are administered.