Thompson Emily R, Bates Lucy, Ibrahim Ibrahim K, Sewpaul Avinash, Stenberg Ben, McNeill Andrew, Figueiredo Rodrigo, Girdlestone Tom, Wilkins Georgina C, Wang Lu, Tingle Samuel J, Scott William E, de Paula Lemos Henrique, Mellor Andrew L, Roobrouck Valerie D, Ting Anthony E, Hosgood Sarah A, Nicholson Michael L, Fisher Andrew J, Ali Simi, Sheerin Neil S, Wilson Colin H
NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK.
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Am J Transplant. 2021 Apr;21(4):1402-1414. doi: 10.1111/ajt.16100. Epub 2020 Jun 28.
Ex vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimize organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC ) possess potent immunomodulatory properties that could minimize ischemia reperfusion injury. We investigated the potential capability of MAPC cells in kidney NMP. Pairs (5) of human kidneys, from the same donor, were simultaneously perfused for 7 hours. Kidneys were randomly allocated to receive MAPC treatment or control. Serial samples of perfusate, urine, and tissue biopsies were taken for comparison. MAPC-treated kidneys demonstrated improved urine output (P = .009), decreased expression of injury biomarker NGAL (P = .012), improved microvascular perfusion on contrast-enhanced ultrasound (cortex P = .019, medulla P = .001), downregulation of interleukin (IL)-1β (P = .050), and upregulation of IL-10 (P < .047) and Indolamine-2, 3-dioxygenase (P = .050). A chemotaxis model demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC-treated kidneys (P < .001). Immunofluorescence revealed prelabeled MAPC cells in the perivascular space of kidneys during NMP. We report the first successful delivery of cellular therapy to a human kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to transplantation.
移植前对供体肾脏进行体外常温机器灌注（NMP）为在移植前直接递送细胞疗法以优化器官质量提供了一个平台。多能成人祖细胞（MAPC）具有强大的免疫调节特性，可将缺血再灌注损伤降至最低。我们研究了MAPC细胞在肾脏NMP中的潜在能力。来自同一供体的5对人肾同时灌注7小时。肾脏被随机分配接受MAPC治疗或对照。采集灌注液、尿液和组织活检的系列样本进行比较。接受MAPC治疗的肾脏尿量增加（P = 0.009），损伤生物标志物NGAL的表达降低（P = 0.012），对比增强超声显示微血管灌注改善（皮质P = 0.019，髓质P = 0.001），白细胞介素（IL）-1β下调（P = 0.050），IL-10上调（P < 0.047）和吲哚胺-2,3-双加氧酶上调（P = 0.050）。趋化模型显示，用来自接受MAPC治疗的肾脏的灌注液刺激时，中性粒细胞募集减少（P < 0.001）。免疫荧光显示在NMP期间肾脏血管周围空间中有预先标记的MAPC细胞。我们报告了在NMP期间首次成功将细胞疗法递送至人肾。接受MAPC细胞治疗的肾脏在临床相关参数和损伤生物标志物方面有所改善。这种新型的细胞疗法递送方法为移植前修复器官提供了一个令人兴奋的机会。
