Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark.
Department of Urology, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Int J Mol Sci. 2022 Jul 27;23(15):8268. doi: 10.3390/ijms23158268.
The immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) make MSC therapy a promising therapeutic strategy in kidney disease. A targeted MSC administration via the renal artery offers an efficient delivery method with limited spillover to other organs. Although local administration alleviates safety issues with MSCs in systemic circulation, it introduces new safety concerns in the kidneys. In a porcine model, we employed intra-renal arterial infusion of ten million allogenic adipose tissue-derived MSCs. In order to trigger any potential adverse events, a higher dose (hundred million MSCs) was also included. The kidney function was studied by magnetic resonance imaging after the MSC infusion and again at two weeks post-treatment. The kidneys were assessed by single kidney glomerular filtration rate (skGFR) measurements, histology and inflammation, and fibrosis-related gene expression. None of the measured parameters were affected immediately after the administration of ten million MSCs, but the administration of one hundred million MSCs induced severe adverse events. Renal perfusion was reduced immediately after MSC administration which coincided with the presence of microthrombi in the glomeruli and signs of an instant blood-mediated inflammatory reaction. At two weeks post-treatment, the kidneys that were treated with one hundred million MSCs showed reduced skGFR, signs of tissue inflammation, and glomerular and tubular damage. In conclusions, the intra-renal administration of ten million MSCs is well-tolerated by the porcine kidney. However, higher concentrations (one hundred million MSCs) caused severe kidney damage, implying that very high doses of intra-renally administered MSCs should be undertaken with caution.
间充质基质细胞 (MSCs) 的免疫调节和再生特性使其成为肾脏疾病治疗的一种很有前途的治疗策略。通过肾动脉靶向 MSC 给药是一种有效的输送方法，对其他器官的溢出有限。虽然局部给药缓解了 MSC 在全身循环中的安全性问题，但它在肾脏中引入了新的安全性问题。在猪模型中，我们采用了经肾动脉内输注 1000 万个同种异体脂肪组织来源的 MSC。为了引发任何潜在的不良反应，还包括了更高剂量（1 亿个 MSC）。在 MSC 输注后和治疗两周后，通过磁共振成像研究肾功能。通过单肾肾小球滤过率 (skGFR) 测量、组织学和炎症以及纤维化相关基因表达来评估肾脏。在输注 1000 万个 MSC 后，立即测量的参数均未受影响，但输注 1 亿个 MSC 会引发严重的不良反应。肾灌注在 MSC 给药后立即减少，这与肾小球中微血栓的存在以及即时血液介导的炎症反应的迹象相吻合。在治疗两周后，接受 1 亿个 MSC 治疗的肾脏显示 skGFR 降低、组织炎症迹象以及肾小球和肾小管损伤。总之，经肾内给予 1000 万个 MSC 可被猪肾脏耐受。然而，更高浓度（1 亿个 MSC）会导致严重的肾脏损伤，这意味着非常高剂量的经肾内给予 MSC 应谨慎进行。
