Treating Ischemically Damaged Porcine Kidneys with Human Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stromal Cells During Ex Vivo Normothermic Machine Perfusion

Abstract

Pre-transplant normothermic machine perfusion (NMP) of donor kidneys offers the unique opportunity to perform active interventions to an isolated renal graft prior to transplantation. There is increasing evidence that mesenchymal stromal cells (MSCs) could have a para-/endocrine regenerative effect on ischaemia-reperfusion injury. The purpose of this study was to determine which cytokines are secreted by MSCs during NMP of a porcine kidney. Viable porcine kidneys and autologous whole blood were obtained from a slaughterhouse. Warm ischaemia time was standardised at 20 min and subsequent hypothermic machine perfusion (HMP) was performed during 2-3 hours. Thereafter, kidneys were machine perfused at 37°C during 7 hours. After 1 hour of NMP either 0, 10 7 cultured human adipose tissue derived MSCs or 10 7 cultured bone-marrow derived MSCs were added (n=5 per group). In a fourth experimental group, 7-hour NMP was performed with 10 7 adipose tissue derived MSCs, without a kidney in the circuit. Kidneys perfused with MSCs showed lower lactate dehydrogenase and neutrophil gelatinase-associated lipocalin levels in comparison with the control group. Also, elevated levels of human HGF, IL-6 and IL-8 were found in the perfusate of the groups perfused with MSCs compared to the control groups.This study suggests that MSCs, in contact with an injured kidney during NMP, could lead to lower levels of injury markers and induce the release of immunomodulatory cytokines.

Combination of mesenchymal stromal cells and machine perfusion is a novel strategy for organ preservation in solid organ transplantation

“…In their subsequent study, they found a significantly increased level of hepatocyte growth factor, together with a decrease in neutrophil gelatinase-associated lipocalin (NGAL) and lactic dehydrogenase in the perfusate. This evidence indicates that Cao et al (2020) the infusion of MSCs during NMP can protect the isolated kidney from ischemic damage (Pool et al 2020).…”

Treatment of transplant kidneys during machine perfusion

“…Experimental evidence for the delivery of MSCs [13–15], gene therapies [28], nanoparticles [30,31] and other IRI targeted [33–39] therapies during NMP is increasing and the results have been positive. However, none of the approaches have been tested in clinical practice.…”

“…However, in the most recent study by the group, they found that the MSCs increased reparative processes in porcine kidneys during NMP. There was an increase in immunomodulatory cytokines (IL‐6 and IL‐8) and hepatocyte growth factor, and a reduction in injury markers, lactate dehydrogenase and neutrophil gelatinase‐associated lipocalin (NGAL) during perfusion [15].…”

Ex Vivo Mesenchymal Stem Cell Therapy to Regenerate Machine Perfused Organs

“…Porcine kidneys challenged with warm ischemia and subsequent HMP were perfused under normothermic conditions for 7 h. After 1 h of NMP, either 10 7 human aMSCs or 10 7 bmMSCs were added. The authors demonstrated that the addition of both types of human MSCs to an ischemically damaged porcine kidney led to an increased release of immunomodulatory cytokines such as human hepatocyte growth factor (HGF), IL-6, and IL-8 into the perfusate, as well as reduced levels of organ injury markers such as lactate dehydrogenase (LDH) and neutrophil gelatinase-associated lipocalin (NGAL), compared to controls without MSC treatment [ 90 ].…”