Role of Renal and Endothelial Progenitors in Fetal Kidney Reconstitution

项目2提出从发育中的人类和非人灵长类动物肾脏中鉴定、分离和繁殖肾祖细胞。这些实验的目的是通过移植具有分化成细胞类型和组织的能力的健康祖细胞来重建和修复患病、受损但正在发育的胎儿肾脏，所述细胞类型和组织将重新填充和重建受影响的器官。这是一个新颖的和临床相关的建议。迄今为止，该领域的工作集中在描述胎儿肾脏阻塞时的变化，但这些努力主要限于出生后啮齿动物的肾脏。我们的单侧输尿管梗阻胎猴模型可以说是研究这种疾病和治疗策略的最佳模型，该提议是由胎儿尿路梗阻的临床状况是影响幼儿肾脏疾病的最重要条件之一这一事实驱动的。本申请中提出的工作汇集了干细胞和祖细胞生物学、胎儿肾脏疾病以及疾病和干预的胎儿模型领域的许多领导者的支持和专业知识。在成功完成本项目中提出的研究后，我们希望我们将准备在患有下尿路梗阻的人类胎儿中进行潜在的干预试验。目前，在北美的许多中心，胎儿被选择用于基于产前母体超声成像的侵入性子宫内胎儿尿路分流。这些干预措施的总体结果有些令人失望，部分原因是患者选择不规范，子宫内诊断不准确，以及对尿路梗阻肾损害发病机制的了解尚未完全。虽然在肾发生的关键时期，在子宫内缓解梗阻的肾脏对优化结局是必要的，但似乎还不够。在阻塞的非人灵长类动物肾脏中使用人类肾脏祖细胞的实验使我们尽可能接近人类干预的下一步。这些后续步骤将由本提案的结果以及随后在人类胎儿中设计良好的随机对照试验的发展来指导。

Project 2 proposes to characterize, isolate, and propagate renal progenitor cells from developing human and from nonhuman primate kidneys. The purpose of these experiments is to enable reconstitution and repair of the diseased, damaged, but developing fetal kidney, by transplanting healthy progenitor cells with the capacity to differentiate into cell types and tissue that will repopulate and reconstitute the affected organ. This is a novel and clinically relevant proposal. Work to date in the field has focused on describing changes in the fetal kidney when obstructed, but these efforts have largely been restricted to the postnatal rodent kidney. Our fetal monkey model of unilateral ureteric obstruction is arguably the best model available to study this disease and strategies to treat it. The proposal is driven by the fact that the clinical condition of fetal urinary tract obstruction is one of the most important conditions affecting young children with kidney disease. The work proposed in this application brings together the support and expertise of a number of leaders in the field of stem and progenitor cell biology, fetal kidney disease, and fetal models of disease and intervention. At the successful completion of the studies proposed in this Project we are hopeful that we will be poised to embark upon potential intervention trials in the human fetus with lower urinary tract obstruction. Presently in many centers across North America, fetuses are selected for invasive in utero fetal urinary tract shunting based upon antenatal maternal ultrasound imaging. The collective results of these interventions have been somewhat disappointing due in part to the non-standardized patient selection, to the inaccuracies of in utero diagnosis, and to an as-yet-complete understanding of the pathogenesis of renal damage in urinary tract obstruction. While in utero relief of the obstructed kidney during the critical time of nephrogenesis is necessary to optimize outcome, it appears that it is likely not sufficient. Experiments proposed using human renal progenitor cells in obstructed nonhuman primate kidneys brings us as close as we can to the next step of intervention in humans. These next steps will be guided by the results of this proposal and by the subsequent development of well-designed randomized controlled trials in human fetuses.