STEM CELL THERAPY FOR ACUTE KIDNEY INJURY

急性肾损伤的干细胞疗法

• 批准号: 7741820
• 负责人: FANGMING LIN
• 金额: $ 37.68万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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/7741820
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adherence; Antibodies; Blocking Antibodies; Bone Marrow; Cadherins; Calcium; Calcium-Sensing Receptors; Cell Therapy; Cell Transplants; Cells; Cessation of life; Collagen; Conditioned Culture Media; Developmental Gene; Down-Regulation; E-Cadherin; Endocrine; Endosteum; Endothelial Cells; Epithelial; Epithelial Cells; Event; Frequencies; Gene Expression Profiling; Genes; Goals; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histone Deacetylase Inhibitor; Homing; In Vitro; Injection of therapeutic agent; Injury; Kidney; Kidney Diseases; Knockout Mice; Laboratories; Lead; Measures; Mediating; Mesenchymal; Microarray Analysis; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Pathway Analysis; Pathway interactions; Proteins; Recovery; Renal function; Renal tubule structure; Sequential Treatment; Source; Stem cells; Stromal Cells; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Transplantation; Trichostatin A; Tubular formation; base; cytokine; effective therapy; gene repression; improved; in vitro Assay; in vivo; injured; kidney cell; migration; mortality; novel strategies; paracrine; public health relevance; renotropic factor; repaired; stem; stem cell therapy

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）：急性肾损伤（阿基）具有较高的发病率和死亡率。目前唯一可用于阿基的治疗包括支持性措施。该项目的总体目标是开发基于干细胞的疗法来治疗阿基。我们先前已经表明，新鲜分离的小鼠造血干细胞（HSC）可以移植并纳入再生肾小管。然而，掺入率低，没有观察到功能益处。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在移植前用细胞因子、肾生成因子和HDAC抑制剂阿司他丁A依次处理以诱导肾分化。诱导的细胞具有肾脏发育基因的重新表达和造血分化基因的下调。注射诱导细胞或诱导细胞条件培养基可改善阿基小鼠的肾功能，表明通过内分泌/旁分泌效应实现肾保护。此外，阻断诱导细胞上的钙敏感受体CaR增加了细胞的肾定位。该结果表明，CaR的调节可能有助于增加细胞的肾内递送以实现更大的治疗效果。为了扩展这些有希望的发现，我们建议用额外的肾脏标志物来表征诱导细胞，以确认肾细胞命运的选择。我们将通过体外试验和移植研究来确定诱导的细胞是否可以分化为功能性肾上皮细胞。将分析细胞转化中涉及的分子途径，以指导发现细胞转化的最佳条件（目标1）。我们将研究诱导细胞是否通过减少内源性肾小管上皮细胞和/或内皮细胞的死亡和增加其增殖来发挥内分泌/旁分泌作用。由于存活的肾小管细胞是肾修复的主要来源，因此诱导细胞释放的肾营养因子可以是治疗阿基的重要药物（目的2）。此外，我们将用抗体阻断CaR或使用CaR缺陷小鼠来测试CaR的调节是否会增加细胞的肾内迁移。该策略可通过增加用于直接细胞替代的肾小管整合和向受损肾小管提供更持续的肾营养因子递送来增加诱导细胞的治疗效用（目的3）。总之，我们采取新的方法来开发细胞治疗剂，通过序贯治疗造血干细胞和祖细胞来治疗阿基，这些造血干细胞和祖细胞可以很容易地获得用于供体定向治疗。公共卫生相关性：叙述急性肾损伤具有高发病率和高死亡率。目前尚无特异有效的治疗方法。干细胞为肾脏疾病提供了治疗潜力。本申请的目的是开发基于干细胞的治疗方法来治疗急性肾损伤。