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一种创新的方法来开发细胞治疗剂，从人类脐带血液衍生的造血干细胞（UCB-HSC）治疗急性肾脏损伤（AKI）。急性肾脏损伤不仅发病率和死亡率很高，而且经常导致慢性肾脏疾病。目前，尚无针对AKI的特定治疗方法。一旦肾脏失败，慢性肾脏疾病的治疗成本为20％的医疗保险支出。新的，更有效的治疗方法，例如基于干细胞的疗法，将对临床和财务影响产生重大影响。我们已经表明，在用细胞因子和体外细胞因子和肾脏基因子治疗1周后，可以将小鼠骨骨髓HSC重编程为表达肾发育基因的细胞。用组蛋白脱乙酰基酶（HDAC）抑制剂Trichostatin A（TSA）进一步治疗细胞的重新编程从6％提高到38％。将重编程的细胞注射到肾脏缺血性损伤中，加速了肾脏结构和功能恢复。为了开始在临床上翻译这些发现，我们建议重新编程人UCB-HSC并在AKI小鼠模型中测试其治疗效果。脐带血含有更高浓度的CD34+茎和祖细胞。可以很容易地将细胞隔离，而没有供体风险。 UTSW附属的Parkland纪念医院每天提供约47名婴儿，以确保隔离细胞的大量供应。使用类似的小鼠骨髓HSC的方法，将通过细胞因子，肾原性因子和HDAC抑制剂TSA在体外治疗来自人类脐带血的CD34+细胞，以诱导造血到肾脏转化。诱导的细胞将以表达肾脏发育基因的表达以及分化为上皮细胞并形成管状结构的能力来表征（AIM 1）。此外，诱导的细胞将被急性缺血再灌注损伤移植到小鼠中，以测试它们是否加速肾功能和结构恢复。通过直接替换为修复小管和/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（AIM 2）。该项目可能代表将干细胞生物学翻译成床边的第一步。我们有信心，凭借我们的经验和奉献精神，我们将能够在最初的9个月中完成AIM 1的研究，并在接下来的15个月中进行AIM 2的研究。 公共卫生相关性：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来自人类脐带血干细胞的细胞治疗剂，以治疗急性肾脏损伤。