Kidney Progenitor Cells in Regenerative Medicine

再生医学中的肾祖细胞

• 批准号: 8712947
• 负责人: VERONIQUE L BARNES
• 金额: $ 14.92万
• 依托单位: PROBETEX, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712947
• 关键词: 3-Dimensional; Acute; Acute Renal Failure with Renal Papillary Necrosis; Area; Biomedical Research; Blood Vessels; Blood capillaries; Bone Marrow; Cell Line; Cell Therapy; Cells; Coculture Techniques; Collecting Cell; Communities; Conditioned Culture Media; Data; Defect; Disease; Disease model; Drops; Duct (organ) structure; Electron Microscopy; Embryo; Endothelial Cells; Epithelial Cells; Epithelium; Experimental Models; Fostering; Glomerular Mesangial Cell; Glomerulonephritis; Grant; Health Sciences; Henle' s loop; Home environment; Human; Implant; Injury; Investigation; Ischemia; Kidney; Kidney Diseases; Licensing; Mesenchymal; Mesenchymal Stem Cells; Mesenchyme; Metanephric Diverticulum; Microscopy; Modality; Modeling; Monitor; Mus; Necrosis; Papillary; Papio; Phase; Primates; Process; Rattus; Reagent; Recovery; Regenerative Medicine; Renal function; Reperfusion Therapy; Replacement Therapy; Research; Research Institute; Resources; Rodent; Role; Services; Source; Stem cells; Structure; Testing; Texas; Therapeutic; Tissue Engineering; Translational Research; Tubular formation; Universities; capillary; cell type; design; differentiation-stimulating factor; established cell line; human disease; improved; infancy; injured; kidney cell; mesangial cell; nephrogenesis; nonhuman primate; paracrine; progenitor; prototype; public health relevance; regenerative; repaired; research study; stem cell biology; stem cell technology; vasculogenesis

Project Summary: We have shown that rat and mouse metanephric mesenchyme (MM) and ureteric bud (UB) cells undergo reciprocal induction to form differentiated tubular epithelium and undergo vasculogenesis forming capillary-like structures in 3-dimensional culture. Because these kidney progenitor cell lines retain differentiation potential, they have enormous potential in state-of-the art areas of research including cell-based therapy, stem cell biology, tissue engineering, and other burgeoning fields in regenerative medicine. This proposal is designed to establish the efficacy of the progenitor cell lines in cell-based therapy to accelerate repair and recovery during acute kidney injury. Information derived from these studies will be used to further commercialize the cells and optimize distribution to the scientific community, fostering investigation in nephrogenesis and regenerative medicine. The following aims are proposed: Aim 1. To define differentiation potential of kidney embryonic progenitor cells in cell-based therapy in acute kidney injury. The therapeutic potential of rodent MM, UB, and glomerular progenitor (GP) cells derived from the nephrogenic zone of the developing kidney will be critically evaluated in cell-based therapy to repair injured structures during acute kidney injury. The ability of the cells to repair tubular and vascular structures via paracrine mechanisms and/or by cell integration will be explored. Three established experimental models of acute kidney injury are selected for proof of concept testing: 1) Ischemia/reperfusion; 2) bromoethylamine hydrobromide (BEA)-induced papillary injury; and 3) Thy- 1-induced mesangioproliferative glomerulonephritis. The models were chosen for their selective damage and drop-out of specialized cell types unique for each disease targeting potential of the progenitor cells to repair proximal tubular cells, the collecting duct, or glomerular mesangial and endothelial cells. Efficacy of cell replacement therapy will be determined by histopathological and functional assessment. Aim 2 will examine the efficacy of secretory products derived from each kidney progenitor cell line as therapeutic modalities to treat acute kidney injury. Aim 2 is designed to examine the efficacy of conditioned medium derived from each of the embryonic progenitor cell lines as therapeutic test agents to accelerate recovery of intrinsic cellular targets in the three models outlined in Aim 1. The active components of the conditioned media in successful experiments will be determined during Phase II. Information derived during the course of this Phase I grant will be used to transition into a subsequent Phase II grant in which corresponding progenitor cells will be isolated from baboon embryonic kidney and used to treat acute kidney injury in non-human primates as a prototype therapy for human disease. Probetex in cooperation with the UTHSCSA and the Southwest National Primate Research Center (SNPRC) at the Texas Biomedical Research Institute (TBRI) has a unique opportunity to procure and test baboon kidney progenitor cells in acute kidney injury in non-human primate models.

项目总结： 我们已经证明，大鼠和小鼠的后肾间充质(MM)和输尿管芽(UB)细胞经历了 相互诱导形成分化的肾小管上皮细胞和血管生成形成毛细血管样 三维培养中的结构。因为这些肾祖细胞系保留了分化潜能， 它们在最先进的研究领域具有巨大的潜力，包括基于细胞的治疗、干细胞 生物学、组织工程学和其他再生医学的新兴领域。这项提议旨在 建立祖细胞系在基于细胞的治疗中加速修复和恢复的有效性 急性肾损伤。从这些研究中获得的信息将被用于进一步商业化细胞和 优化向科学界的分布，促进肾脏发生和再生的研究 医药。目的1.明确肾脏胚胎的分化潜能 祖细胞在急性肾损伤细胞治疗中的应用。啮齿动物MM、UB、 来自发育中肾脏的肾成区的肾小球祖细胞(GP)将被 在急性肾损伤期间修复受损结构的基于细胞的治疗方面进行了严格的评估。美国人的能力 通过旁分泌机制和/或细胞整合修复肾小管和血管结构的细胞将 探索过了。选择三种已建立的急性肾损伤实验模型进行概念验证。 检测：1)缺血/再灌注；2)溴乙胺(BEA)诱导的乳头肌损伤；3)Thy- 1诱导的系膜增生性肾小球肾炎。选择这些型号是因为它们的选择性损害和 每种疾病特有的特定细胞类型的缺失以祖细胞修复的潜力为目标 近端肾小管细胞、集合管或肾小球系膜细胞和内皮细胞。细胞的功效 替代疗法将通过组织病理学和功能评估来确定。Aim 2将检查 不同肾祖细胞系分泌产物的治疗作用 治疗急性肾损伤的方法。《目标2》旨在检验条件培养液的功效。 从每个胚胎祖细胞系中提取的作为治疗测试剂以加速恢复 目标1中概述的三个模型中的固有细胞靶点：条件培养液的活性成分 成功的实验将在第二阶段确定。在此过程中获得的信息 第一阶段赠款将用于过渡到随后的第二阶段赠款，在第二阶段赠款中，相应的祖先 将从狒狒胚胎肾脏中分离细胞用于治疗非人类急性肾损伤 灵长类动物作为人类疾病的原型疗法。Probetex与UTHSCSA和 德克萨斯生物医学研究所西南国家灵长类研究中心(SNPRC)已经 在非人类急性肾损伤中获取和检测狒狒肾祖细胞的独特机会 灵长类模型。