Perfusion of isolated rat kidney with Mesenchymal Stromal Cells/Extracellular Vesicles prevents ischaemic injury

Abstract

Kidney donation after circulatory death (DCD) is a less than ideal option to meet organ shortages. Hypothermic machine perfusion (HMP) with Belzer solution (BS) improves the viability of DCD kidneys, although the graft clinical course remains critical. Mesenchymal stromal cells (MSC) promote tissue repair by releasing extracellular vesicles (EV). We evaluated whether delivering MSC‐/MSC‐derived EV during HMP protects rat DCD kidneys from ischaemic injury and investigated the underlying pathogenic mechanisms. Warm ischaemic isolated kidneys were cold‐perfused (4 hrs) with BS, BS supplemented with MSC or EV. Renal damage was evaluated by histology and renal gene expression by microarray analysis, RT‐PCR. Malondialdehyde, lactate, LDH, glucose and pyruvate were measured in the effluent fluid. MSC‐/EV‐treated kidneys showed significantly less global ischaemic damage. In the MSC/EV groups, there was up‐regulation of three genes encoding enzymes known to improve cell energy metabolism and three genes encoding proteins involved in ion membrane transport. In the effluent fluid, lactate, LDH, MDA and glucose were significantly lower and pyruvate higher in MSC/EV kidneys as compared with BS, suggesting the larger use of energy substrates by MSC/EV kidneys. The addition of MSC/EV to BS during HMP protects the kidney from ischaemic injury by preserving the enzymatic machinery essential for cell viability and protects the kidney from reperfusion damage.

Potential Applications of Extracellular Vesicles in Solid Organ Transplantation

“…Histological and genetic analyses on EV-treated kidneys revealed upregulation of enzymes involved in energy metabolism and reduction of global ischemic damage. In addition, the analysis of lactate, LDH, and glucose in the effluent fluid confirmed a greater use of energy substrates by EV-treated kidneys, supporting the report of improved functionality (Table 1) [58].…”

Exosomes and microvesicles in normal physiology, pathophysiology, and renal diseases

“…These effects have been documented in vitro [228] and in vivo [229] and are attributed to the transfer of both growth factors and RNAs (mRNAs and miRNAs) [230]. As described above, EVs can stimulate angiogenesis, and transfer growth factors such as vascular endothelial growth factor, hepatocyte growth factor [231], insulin-like growth factor-1 (IGF-1), adrenomedullin, and stromal cell-derived factor-1 (SDF1) [4].…”

Impact of Mesenchymal Stromal Cells and Their Extracellular Vesicles in a Rat Model of Kidney Rejection

“…A large number of studies had been focusing on the application of MSCs from different sources in kidney transplants, and few studies have compared allogeneic versus autologous MSC therapy to determine its beneficial effects on renal rejection outcome. Moreover, stem cell-derived EVs are described as a new therapeutic option for renal injury, but their application in pre-clinical models is only related to avoiding renal damage during the organ reperfusion prior to transplant (Gregorini et al, 2017;Rigo et al, 2018). Here, we have evaluated the immunomodulatory properties of MSCs isolated from adipose tissue (AD) or bone marrow (BM) and their EVs within autologous and donor-derived settings, on kidney outcome in a rat model of kidney rejection without immunosuppression associated.…”