Ex Vivo Mesenchymal Stem Cell Therapy to Regenerate Machine Perfused Organs

Abstract

Transplantation represents the treatment of choice for many end-stage diseases but is limited by the shortage of healthy donor organs. Ex situ normothermic machine perfusion (NMP) has the potential to extend the donor pool by facilitating the use of marginal quality organs such as those from donors after cardiac death (DCD) and extended criteria donors (ECD). NMP provides a platform for organ quality assessment but also offers the opportunity to treat and eventually regenerate organs during the perfusion process prior to transplantation. Due to their anti-inflammatory, immunomodulatory and regenerative capacity, mesenchymal stem cells (MSCs) are considered as an interesting tool in this model system. Only a limited number of studies have reported on the use of MSCs during ex situ machine perfusion so far with a focus on feasibility and safety aspects. At this point, no clinical benefits have been conclusively demonstrated, and studies with controlled transplantation set-ups are urgently warranted to elucidate favorable effects of MSCs in order to improve organs during ex situ machine perfusion.

What Is Hot and New in Basic and Translational Science in Liver Transplantation in 2023? Report of the Basic and Translational Research Committee of the International Liver Transplantation Society

“…We believe that MP technology has certainly improved organ preservation protocols-the challenge now is to use this technology as a platform to reliably assess organ viability and improve quality and function of organs by delivering treatments such as defatting cocktails, cellular, and genetic treatments, such as siRNA and/or CRISPR gene editing during infusion sessions. [61][62][63][64][65] Similarly, an improved understanding of the mechanisms and pathways associated with liver fibrosis and regeneration is critical to the development of innovative therapies to block the progression of fibrosis and stimulate regeneration. Organoid development can be used not only to answer these questions but also to understand the mechanisms involved in the development of biliary lesions, liver tumors, and recurrence of immune associated liver diseases after transplantation, among others.…”

Extracellular Vesicles as Drug Delivery Systems in Organ Transplantation: The Next Frontier

“…Machine perfusion of organs outside the body prior to transplantation has been introduced to mitigate IRI and not only enables graft viability assessment [ 158 , 159 ] but also the delivery of therapeutics for the repair of organs prior to transplantation ( Figure 3 ) [ 160 ]. The efficacy of MSC delivery during perfusion to mitigate IRI has been demonstrated in several organ systems [ 161 , 162 , 163 ].…”

Ex-vivo Kidney Machine Perfusion: Therapeutic Potential

“…Mesenchymal stromal cells (MSC) are multipotent cells mainly derived from bone marrow and adipose tissue, but also present in the umbilical cord, placenta, peripheral blood, and other tissues. Due to their stem-celllike properties, after the engraftment into organs, they can differentiate into various functional cells and interfere with detrimental pathophysiological processes (124). International Society for Cellular Therapy established criteria defining MSC, including plastic-adherence when maintained in standard culture conditions, expression of cluster of differentiation (CD)73, CD90, and CD105 surface markers, lack of expression of endothelial and blood cell markers CD45, CD34, CD14 or CD11b, CD79α or CD19, and human leukocyte antigen (HLA)-DR, and capacity to differentiate into osteoblasts, chondroblasts, and adipocytes in vitro (125).…”

“…International Society for Cellular Therapy established criteria defining MSC, including plastic-adherence when maintained in standard culture conditions, expression of cluster of differentiation (CD)73, CD90, and CD105 surface markers, lack of expression of endothelial and blood cell markers CD45, CD34, CD14 or CD11b, CD79α or CD19, and human leukocyte antigen (HLA)-DR, and capacity to differentiate into osteoblasts, chondroblasts, and adipocytes in vitro (125). Low immunogenicity (the lack of HLA class II expression, low HLA class I and costimulatory molecules expression), immunomodulatory and regenerative properties, as well as unelaborate growth in vitro (126) make MSC an attractive therapeutic agent in the field of solid organ Tx (124,127). Like stem cells, they are able to differentiate into specified cells or deliver organelles to injured cells and consequently restore the function of the damaged organ (128).…”