STEM CELL THERAPY FOR ACUTE KIDNEY INJURY

急性肾损伤的干细胞疗法

• 批准号: 8254902
• 负责人: FANGMING LIN
• 金额: $ 17.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254902
• 关键词: STEM; CELL; THERAPY; ACUTE; KIDNEY

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) carries high morbidity and mortality. The only treatment that is currently available for AKI consists of supportive measures. The overall goal of this project is to develop stem cell- based therapy to treat AKI. We have previously shown that freshly isolated mouse hematopoietic stem cells (HSC) can be transplanted and incorporated into regenerating renal tubules. However, the incorporation rate is low and no functional benefit is observed. To enhance the therapeutic potential of HSC, we have developed a novel approach in which hematopoietic stem and progenitor cells are treated sequentially with cytokines, nephrogenic factors, and an HDAC inhibitor trichostatin A to induce renal differentiation prior to transplantation. Induced cells have de novo expression of renal developmental genes and down-regulation of hematopoietic differentiation genes. Injection of induced cells or induced cell-conditioned medium improves renal function in mice with AKI, suggesting renal protection by endocrine/paracrine effects. Furthermore, blocking the calcium sensing receptor, CaR, on induced cells increases renal localization of the cells. This result suggests that modulation of the CaR may be useful to increase intrarenal delivery of the cells to achieve greater therapeutic effects. To extend these promising findings, we propose to characterize induced cells with additional renal markers to confirm the selection of renal cell fate. We will determine whether induced cells can differentiate into functional renal epithelial cells by in vitro assays and transplantation studies. The molecular pathways involved in cell conversion will be analyzed to guide the discovery of optimal conditions for cell conversion (Aim 1). We will examine whether induced cells exert endocrine/paracrine effects by decreasing death and increasing proliferation of endogenous tubular epithelial cells and/or endothelial cells. Since surviving tubular cells are the main source for renal repair, renotrophic factors released by induced cells can be important agents to treat AKI (Aim 2). Furthermore, we will block the CaR with an antibody or use CaR-deficient mice to test whether modulation of the CaR could increase intrarenal transmigration of the cells. This strategy may increase the therapeutic utility of induced cells by increasing tubular integration for direct cell replacement and providing more sustained delivery of renotrophic factors to the injured tubules (Aim 3). In conclusion, we take novel approaches to develop cell therapeutic agents to treat AKI by sequential treatment of hematopoietic stem and progenitor cells that can be obtained easily for donor-directed therapy. PUBLIC HEALTH RELEVANCE: Narrative Acute kidney injury has high morbidity and high mortality. There is no specific and effective treatment at present time. Stem cells offer therapeutic potential for kidney disease. The goal of this application is to develop stem cell-based therapy to treat acute kidney injury.

描述（由申请人提供）：急性肾脏损伤（AKI）具有高发病率和死亡率。当前可用于AKI的唯一治疗方法是支持措施。该项目的总体目标是开发基于干细胞的治疗以治疗AKI。我们先前已经表明，新鲜分离的小鼠造血干细胞（HSC）可以移植并掺入再生肾小管中。但是，掺入速率很低，未观察到功能益处。为了增强HSC的治疗潜力，我们开发了一种新的方法，其中造血干细胞和祖细胞用细胞因子，肾原料因子和HDAC抑制剂Trichostatin A顺序治疗，以诱导移植前诱导肾脏分化。诱导的细胞具有从头表达的肾脏发育基因和造血分化基因的下调。注射诱导的细胞或诱导细胞调节培养基可改善AKI小鼠的肾功能，表明通过内分泌/旁分泌作用肾脏保护。此外，在诱导细胞上阻断钙传感受体，CAR，会增加细胞的肾脏定位。该结果表明，对汽车的调节可能有助于增加细胞内递送以获得更大的治疗作用。为了扩展这些有希望的发现，我们建议用其他肾脏标记表征诱导的细胞，以确认肾细胞命运的选择。我们将通过体外测定和移植研究确定诱导的细胞是否可以区分功能性肾上皮细胞。将分析参与细胞转换的分子途径，以指导发现细胞转换的最佳条件（AIM 1）。我们将检查诱导的细胞是否通过减少死亡并增加内源性管状上皮细胞和/或内皮细胞的增殖来发挥内分泌/旁分泌作用。由于存活的管状细胞是肾脏修复的主要来源，因此诱导细胞释放的肾营养因子可能是治疗AKI的重要药物（AIM 2）。此外，我们将使用抗体阻止汽车，或使用缺陷型汽车的小鼠测试汽车的调节是否可以增加细胞的肾内跨迁移。该策略可以通过增加管状整合以直接替代细胞并为受伤的肾小管提供更持续的肾量输送（AIM 3）来增加诱导细胞的治疗效用（AIM 3）。总之，我们采用新颖的方法来开发细胞治疗剂，通过顺序治疗造血干细胞和祖细胞来治疗AKI，这些细胞可以很容易地用于供体指导的治疗。公共卫生相关性：叙事性急性肾脏损伤具有高发病率和高死亡率。目前没有具体有效的治疗方法。干细胞为肾脏疾病提供治疗潜力。该应用的目的是开发基于干细胞的疗法来治疗急性肾脏损伤。