Use of Umbilical Core Blood derived HSC to Treat Acute Kidney Injury

使用脐带血造血干细胞治疗急性肾损伤

• 批准号: 7832028
• 负责人: FANGMING LIN
• 金额: $ 29.83万
• 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: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7832028
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Aorta; Area; Autologous; Blood; Blood Banks; Bone Marrow; CD34 gene; Cell Separation; Cell Therapy; Cells; Chronic Kidney Failure; Clinical; Cost of Illness; Dedications; Developmental Gene; End stage renal failure; Ensure; Epigenetic Process; Epithelial; Epithelial Cells; Ethics; Expenditure; Goals; Gonadal structure; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Histone Deacetylase; Histone Deacetylase Inhibitor; Hospitals; Human; Immunodeficient Mouse; Immunosuppression; In Vitro; Incidence; Infant; Injection of therapeutic agent; Injury; Kidney; Kidney Diseases; Lead; Measures; Medicare; Mesenchymal; Mesonephric structure; Monitor; Morbidity - disease rate; Mus; Natural regeneration; Phenotype; Quality of life; Recovery; Recovery of Function; Regenerative Medicine; Reperfusion Injury; Risk; Safety; Site; Stem cells; Structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Tissues; Translating; Translations; Transplantation; Trichostatin A; Tubular formation; Umbilical Cord Blood; clinical application; cytokine; effective therapy; experience; improved; innovation; kidney cell; mortality; mouse model; paracrine; programs; public health relevance; repaired; small molecule; stem; stem cell biology

DESCRIPTION (provided by applicant): The overall goal of this project is to take an innovative approach to develop cell therapeutic agents from human umbilical cord blood-derived hematopoietic stem cells (UCB-HSC) to treat acute kidney injury (AKI). Acute kidney injury not only has a high morbidity and mortality rate but often leads to chronic kidney disease. At the present time, there is no specific treatment for AKI. Once the kidney fails, treatment of chronic kidney disease costs 20% Medicare expenditure. New and more effective treatments, such as stem cell-based therapy, will have significant clinical and financial impact. We have shown that mouse bone marrow HSC can be reprogrammed into cells expressing renal developmental genes after 1 week of treatment with cytokines and nephrogenic factors in vitro. Further treatment of the cells with a histone deacetylase (HDAC) inhibitor trichostatin A (TSA) enhances reprogramming from 6% to 38%. Injection of the reprogrammed cells into mice with renal ischemic injury accelerates kidney structural and functional recovery. To begin to translate these findings clinically, we propose to reprogram human UCB- HSC and test their therapeutic effect in mouse models of AKI. Umbilical cord blood contains higher concentrations of CD34+ stem and progenitor cells. The cells can be isolated easily without risk to the donors. The UTSW-affiliated Parkland Memorial Hospital delivers about 47 infants a day, which ensures an abundant supply for cell isolation. Using a similar approach for the mouse bone marrow HSC, CD34+ cells from human umbilical cord blood will be treated in vitro with cytokines, nephrogenic factors and a HDAC inhibitor TSA to induce hematopoietic-to-renal conversion. The induced cells will be characterized for the expression of a panel of renal developmental genes, and their ability to differentiate into epithelial cells and form tubular structures (Aim 1). Furthermore, the induced cells will be transplanted into mice with acute ischemia-reperfusion injury to test whether they accelerate renal functional and structural recovery. The mechanisms of renal protection by direct cell replacement into the repairing tubules and/or paracrine effect to decrease epithelial and endothelial injury and increase intrinsic renal cell regeneration will be investigated (Aim 2). This project may represent the first step toward translation of stem cell biology to the bedside. We are confident that with our experience and dedication, we will be able to complete the studies in Aim 1 in the first 9 months and the studies in Aim 2 in the next 15 months. PUBLIC HEALTH RELEVANCE: Acute kidney injury has high morbidity and high mortality. There is no specific and effective treatment at the present time. Stem cells offer therapeutic potential for kidney disease. The goal of this application is to develop cell therapeutic agents from human umbilical cord blood-derived stem cells to treat acute kidney injury.

描述（由申请人提供）：该项目的总体目标是采用创新方法从人脐带血源性造血干细胞（UCB-HSC）中开发细胞治疗剂来治疗急性肾损伤（AKI）。急性肾损伤不仅发病率和死亡率较高，而且常导致慢性肾脏病。目前，AKI 尚无特效治疗方法。一旦肾功能衰竭，慢性肾病的治疗费用将占医疗保险支出的20%。新的更有效的治疗方法，例如基于干细胞的治疗，将产生重大的临床和财务影响。我们已经证明，在体外用细胞因子和肾生成因子治疗1周后，小鼠骨髓HSC可以重编程为表达肾发育基因的细胞。用组蛋白脱乙酰酶 (HDAC) 抑制剂曲古抑菌素 A (TSA) 进一步处理细胞，可将重编程能力从 6% 增强至 38%。将重编程的细胞注射到肾缺血损伤的小鼠体内可加速肾脏结构和功能的恢复。为了开始将这些发现转化为临床，我们建议重新编程人类 UCB-HSC 并在 AKI 小鼠模型中测试其治疗效果。脐带血含有较高浓度的 CD34+ 干细胞和祖细胞。细胞可以轻松分离，不会给捐赠者带来风险。 UTSW 附属帕克兰纪念医院每天接生约 47 名婴儿，这确保了细胞分离的充足供应。采用与小鼠骨髓 HSC 类似的方法，来自人脐带血的 CD34+ 细胞将在体外用细胞因子、肾生成因子和 HDAC 抑制剂 TSA 进行处理，以诱导造血向肾脏的转化。诱导细胞的特征在于一组肾脏发育基因的表达，以及它们分化为上皮细胞和形成管状结构的能力（目标 1）。此外，诱导的细胞将被移植到急性缺血再灌注损伤的小鼠体内，以测试它们是否加速肾功能和结构的恢复。将研究通过直接细胞替换到修复肾小管和/或旁分泌效应来减少上皮和内皮损伤并增加内在肾细胞再生的肾脏保护机制（目标2）。该项目可能代表着干细胞生物学向临床转化的第一步。我们有信心，凭借我们的经验和奉献精神，我们将能够在前 9 个月内完成目标 1 的学习，并在未来 15 个月内完成目标 2 的学习。 公众健康相关性：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。该应用的目标是利用人脐带血干细胞开发细胞治疗剂来治疗急性肾损伤。