Mesenchymal Stromal Cells Are Retained in the Porcine Renal Cortex Independently of Their Metabolic State After Renal Intra-Arterial Infusion

Abstract

The regenerative capacities of mesenchymal stromal cells (MSC) make them suitable for renal regenerative therapy. The most common delivery route of MSC is via intravenous infusion, which is associated with off-target distribution. Renal intra-arterial delivery offers a targeted therapy but limited knowledge is available regarding the fate of MSC delivered via this route. Therefore, we studied the efficiency and tissue distribution of MSC after renal intra-arterial delivery to a porcine renal ischemia reperfusion model. MSC were isolated from adipose tissue of healthy male pigs, fluorescently labelled and infused into the renal artery of female pigs. Flow cytometry allowed MSC detection and quantification in tissue and blood. In addition, qPCR was used to trace MSC by their Y-chromosome. During infusion, a minor number of MSC left the kidney via the renal vein and no MSC were identified in arterial blood. Ischemic and healthy renal tissue were analyzed 30 minutes and 8 hours after infusion and 1-4 x 10 4 MSC per gram of tissue were detected, predominantly, in the renal cortex, with a viability greater than 70%. Confocal microscopy demonstrated mainly glomerular localization of MSC, but they were also observed in the capillary network around tubuli. The infusion of heat inactivated (HI)-MSC, which are metabolically inactive, through the renal artery showed that HI-MSC were distributed in the kidney in a similar manner as regular MSC, suggesting a passive retention mechanism. Long term MSC survival was analyzed by Y-chromosome tracing and demonstrated that a low percentage of the infused MSC were present in the kidney 14 days after administration, while HI-MSC were completely undetectable.In conclusion, renal intra-arterial MSC infusion limited off-target engraftment, leading to efficient MSC delivery to the kidney, most of them being cleared within 14 days. MSC retention was independent of the metabolic state of MSC, indicating a passive mechanism.

Reparative effect of mesenchymal stromal cells on endothelial cells after hypoxic and inflammatory injury

“…However, the fate of MSC administered in this manner to the kidney is unclear. We previously reported a sharp decline in the number of MSC present in kidney biopsies at 2 weeks after administration of MSC [23]. It is expected that MSC would not stay at the luminal side of microcapillaries, but that these cells are either removed by innate immune cells or migrate to other sites [13,47].…”

“…Thus, direct MSC infusion to the injured tissue may be a better method to deliver MSC to the kidney. We have previously shown that for infusion via the renal artery, MSC are delivered to the microvasculature of the kidney [23]. The interaction with the kidney microvasculature is the starting point for the regenerative effects of MSC, and therefore, it is of key importance to understand the mechanisms of the interaction between MSC and endothelial cells.…”

Mesenchymal stromal cell–based therapies for acute kidney injury: progress in the last decade

“…29 Similarly, Sierra-Parraga et al recently demonstrated in a pig model of renal IRI that intrarenal arterial infusion of adipose-derived MSC resulted in significant retention up to 8 hours postinfusion, primarily in an intraglomerular distribution with smaller numbers in peritubular capillaries. 30 Although biodistribution results from animal models are likely to be relevant to human subjects, there remains a persistent gap in knowledge of the optimal administration protocols for MSC therapies in AKI.…”

Reparative Effect of Mesenchymal Stromal Cells on Endothelial Cells after Hypoxic and Inflammatory Injury

“…However, the fate of MSC administered in this manner to the kidney is unclear. We previously reported a sharp decline in the number of MSC present in kidney biopsies at 2 weeks after administration of MSC (23). It is expected that MSC would not stay at the luminal side of microcapillaries, but that these cells are either removed by innate immune cells or migrate to other sides (13,47).…”

“…Thus, direct MSC infusion to the injured tissue may be a better method to deliver MSC to the kidney. We have previously shown that infusion via the renal artery, MSC are delivered to the microvasculature of the kidney (23). The interaction with the kidney microvasculature is the starting point for the regenerative effects of MSC and therefore it is of key importance to understand the mechanisms of the interaction between MSC and endothelial cells.…”