Application of progenitor niche signals to ex vivo nephrogenesis

祖细胞生态位信号在离体肾发生中的应用

• 批准号: 9981392
• 负责人: Thomas Joseph Carroll
• 金额: $ 101.19万
• 依托单位: ROGOSIN INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981392
• 关键词: 3-Dimensional; Acute Renal Failure with Renal Papillary Necrosis; American; Architecture; Biocompatible Materials; Biomedical Engineering; Blood Vessels; Cell Differentiation process; Cell Proliferation; Cells; Chronic Kidney Failure; Clinical; Collaborations; Cues; Data; Development; Devices; Dialysis procedure; Dimensions; Embryo; End stage renal failure; Endothelial Cells; Endothelium; Engineering; Engraftment; Environment; Epithelium; Equilibrium; Excision; Extracellular Matrix; Fibroblast Growth Factor; Formulation; Generations; Goals; Group Meetings; Health; Human; In Vitro; Individual; Investigation; Kidney; Kidney Transplantation; Laboratories; Life; Longevity; Metanephric Diverticulum; Mus; Nature; Nephrons; Organ; Organ Transplantation; Organogenesis; Pathway interactions; Patients; Pattern; Physiological; Physiology; Population Heterogeneity; Process; Proteins; Recording of previous events; Regenerative response; Renal Replacement Therapy; Renal Tissue; Renal function; Research; Research Personnel; Scaffolding Protein; Schedule; Signal Pathway; Signal Transduction; Silk; Stem cells; Structure; Survival Rate; System; Testing; Tissues; Vascularization; Work; base; cell type; human embryonic stem cell; human stem cells; in vivo; injured; innovation; innovative technologies; interstitial cell; meetings; nephrogenesis; novel; novel therapeutics; progenitor; programs; public health relevance; repaired; scaffold; self-renewal; three dimensional cell culture; tool; web site

 DESCRIPTION (provided by applicant): Approximately 500,000 Americans have end stage renal disease, in which kidney function is insufficient to sustain life. Organ function can be supplemented by dialysis in these individuals; however the 10 year survival rate for individuals on dialysis is just over 10%. Survival rates are much better for patients receiving a kidney transplant but organ supply does not match demand. Ex vivo organogenesis has the potential both to provide functional tissue for renal replacement therapy and to provide research tools with which we can understand the causes of chronic kidney disease and identify new therapies. Furthermore, defining signals that functionally direct nephrogenesis may identify pathways that can be manipulated to augment the regenerative response of the injured kidney in vivo. Our group is able to promote nephrogenesis in cultures of purified primary nephron progenitor cells derived from human stem cells and mouse embryonic kidneys. However, we have identified two key obstacles that must be overcome if this discovery is to have significant impact on human health. First, we must recreate signaling environments that promote progenitor cell proliferation and differentiation in order to obtain sufficient tubule mass for functional analysis. Second, we must devise ex vivo tissue architecture that supports differentiation of arrayed nephrons with vascular connections that are appropriately patterned. The long-term goal of this proposal is to define the tissue architecture and cell signaling microenvironments required to promote the generation of appropriately patterned nephrons in culture. We will investigate signaling mechanisms that are sufficient to promote NPC renewal and differentiation and apply these findings to the development of ex vivo nephron devices using silk protein as a scaffolding biomaterial. Our data show that NPCs efficiently colonize silk and that nephron tubules form in this material. Silk is the material of choice because it is already in clinical use and it is scalale, allowing us to generate structures dimensioned for mouse or human. We will leverage the strengths of the project investigators in kidney and endothelial development as well as bioengineering to develop an integrated, multi-cellular, patterned, functional nephron in vitro. State of the art, innovative technologies will be applied to NPCs differentiated from both human embryonic stem cells and embryonic mouse kidneys. Novel scaffolding and matrix formulations that allow organized 3D organogenesis of tissues in culture will be explored. The investigative group has a 10-year history of collaboration, which is particularly evident in the integrated natur of our preliminary data. We will leverage this program to develop a seamless exchange of engineering and signaling expertise, materials and intellectual innovation between all four laboratories. The program therefore includes a framework for continual scientific exchange including a data tracking website, a bi-monthly schedule of group meetings and face-to-face meetings approximately every 6 months.

 描述（申请人提供）：大约有 500,000 名美国人患有终末期肾病，这些人的肾功能不足以维持生命，可以通过透析来补充器官功能；然而，透析患者的 10 年生存率刚刚结束。接受肾移植的患者的存活率要高得多，但离体器官发生有可能为肾脏替代治疗提供功能组织。提供研究工具，使我们能够了解慢性肾脏疾病的原因并确定新的疗法，此外，定义功能性指导肾发生的信号可能会确定可操纵以增强受损肾脏体内再生反应的途径。然而，如果这一发现要对人类健康产生重大影响，我们已经确定了必须克服的两个关键障碍。其次，我们必须设计出支持具有适当模式的血管连接的阵列肾单位分化的离体组织结构。该提案的目的是定义促进培养中适当模式肾单位生成所需的组织结构和细胞信号传导微环境，我们将研究足以促进 NPC 更新和分化的信号传导机制，并将这些发现应用于离体发育。我们的数据表明，NPC 可以有效地在丝中定植，并且在这种材料中形成肾单位小管，因为它已经在临床使用，并且具有可扩展性，使我们能够生成结构。我们将利用项目研究人员在肾脏和内皮发育以及生物工程方面的优势，在体外开发出一种集成的、多细胞的、模式化的功能性肾单位。该技术将应用于从人类胚胎干细胞和小鼠胚胎肾脏中分化出来的 NPC，该研究小组将探索能够在培养物中进行有组织的 3D 器官发生的新型支架和基质配方。我们将利用该计划在所有四个实验室之间开发工程和信号专业知识、材料和智力创新的无缝交流，这一点在我们初步数据的综合性质中尤为明显。持续的科学交流，包括数据跟踪网站、每两个月举行一次的小组会议以及大约每 6 个月一次的面对面会议。

项目成果

The bioengineered kidney: science or science fiction?

• DOI: 10.1097/mnh.0000000000000235
• 发表时间: 2016-07
• 期刊: Current opinion in nephrology and hypertension
• 影响因子: 3.2
• 作者: Oxburgh L;Carroll TJ
• 通讯作者: Carroll TJ