Role of Renal and Endothelial Progenitors in Fetal Kidney Reconstitution

项目2建议从发育中的人类和非人类灵长类肾脏中鉴定、分离和繁殖肾祖细胞。这些实验的目的是通过移植健康的祖细胞来重建和修复患病、受损但正在发育的胎儿肾脏，这些细胞具有分化为细胞类型和组织的能力，这些细胞和组织将重新填充和重建受影响的器官。这是一项新颖且具有临床意义的建议。到目前为止，该领域的工作主要集中在描述胎儿肾脏在受阻时的变化，但这些努力在很大程度上局限于出生后的啮齿动物肾脏。我们的单侧输尿管梗阻的胚胎猴模型可以说是研究这种疾病和治疗策略的最佳模型。提出这一建议的原因是，胎儿尿路梗阻的临床状况是影响患有肾脏疾病的幼儿的最重要条件之一。这项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、胎儿疾病模型和干预领域的许多领导者的支持和专业知识。在本项目建议的研究成功完成后，我们有望开始对患有下尿路梗阻的人类胎儿进行潜在的干预试验。目前，在北美的许多中心，胎儿是根据产前母体超声成像选择进行侵袭性宫内胎儿尿路分流术的。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标准化，宫内诊断不准确，以及对尿路梗阻肾损害的发病机制尚未完全了解。虽然在肾脏形成的关键时期对梗阻肾进行宫内缓解是优化预后所必需的，但似乎这可能是不够的。建议在受阻的非人类灵长类动物肾脏中使用人类肾祖细胞的实验使我们尽可能接近在人类身上进行干预的下一步。这些后续步骤将以这一提议的结果和随后设计良好的人类胚胎随机对照试验的发展为指导。

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.