Mesenchymal stromal cells are retained in the porcine renal cortex independently of their metabolic state after renal intra-arterial infusion

TY - JOUR

T1 - Mesenchymal stromal cells are retained in the porcine renal cortex independently of their metabolic state after renal intra-arterial infusion

AU - Sierra-Parraga, Jesus Maria

AU - Munk, Anders

AU - Schmidt Andersen, Christine

AU - Lohmann, Stine

AU - Moers, Cyril

AU - Baan, Carla C

AU - Ploeg, Rutger

AU - Pool, Merel

AU - Krarup Keller, Anna

AU - Møller, Bjarne

AU - Leuvenink, Henri

AU - Hoogduijn, Martin J

AU - Jespersen, Bente

AU - Eijken, Marco

PY - 2019/9

Y1 - 2019/9

N2 - 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 104 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.

AB - 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 104 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.

KW - cell therapy

KW - ischemia-reperfusion injury

KW - mesenchymal stromal cells

KW - porcine model

KW - renal intra-arterial

U2 - 10.1089/scd.2019.0105

DO - 10.1089/scd.2019.0105

M3 - Journal article

C2 - 31280676

SN - 1547-3287

VL - 28

SP - 1224

EP - 1235

JO - Stem Cells and Development

JF - Stem Cells and Development

IS - 18

ER -