Renal repair effects of senolytic preconditioned mesenchymal stromal cells in diabetic kidney disease

senolytic 预处理间充质基质细胞对糖尿病肾病的肾修复作用

• 批准号: 10092153
• 负责人: LaTonya J Hickson
• 金额: $ 23.79万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-25 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092153
• 关键词: Adipocytes; Adipose tissue; Affect; Age; Aging; Albuminuria; Allogenic; Angiotensin II; Anti-Inflammatory Agents; Apoptotic; Autologous; Blood; Blood flow; CCL2 gene; Cell Aging; Cell Proliferation; Cell Therapy; Cell physiology; Cells; Chronic Disease; Clinical Trials; Collagen Type I; Country; Crohn' s disease; DNA Damage; Dasatinib; Development; Diabetic Nephropathy; Disease; Disease Progression; Down-Regulation; E-Cadherin; Elements; Epithelial Cells; Excision; Exhibits; Fibrosis; Flavonoids; Functional disorder; Future; Genes; Glucose; Goals; Harvest; Health; Human; Hypertension; Hypoxia; Immune mediated destruction; In Vitro; Individual; Inflammation; Inflammatory; Infusion procedures; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Lead; Magnetic Resonance Imaging; Measures; Mediating; Methods; Microalbuminuria; Modeling; Mus; Natural regeneration; Oral; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Pilot Projects; Progressive Disease; Quercetin; Randomized; Refractory; Regimen; Renal function; Renal tubule structure; Research Design; Resistance; Safety; Sampling; Signal Transduction; Stem cell transplant; Testing; Therapeutic; Therapy Clinical Trials; Therapy trial; Transforming Growth Factor beta; Translations; Tyrosine Kinase Inhibitor; Urine; Work; bench to bedside; cytokine; db/db mouse; diabetic; effective therapy; epithelial to mesenchymal transition; first-in-human; glomerulosclerosis; graft vs host disease; immunoregulation; improved; in vivo; injury and repair; innovation; kidney cell; kidney preservation; kidney vascular structure; mesenchymal stromal cell; mouse model; non-diabetic; novel; open label; paracrine; pilot trial; preconditioning; prevent; programs; regenerative; renal damage; repaired; reparative capacity; response; risk minimization; safety testing; senescence; sex; stem cell function; stem cell therapy; stem cells; tissue injury; tissue regeneration

ABSTRACT / PROJECT SUMMARY Diabetic kidney disease (DKD), the leading driver of the global burden of kidney disease, is resistant to most treatment options. Thus, development of effective therapies to slow the progression of DKD is crucial. Mesenchymal stromal cells (MSC), approved for treating refractory inflammatory diseases elsewhere, possess paracrine anti-fibrotic, anti-apoptotic, pro-angiogenic and immunomodulatory regenerative activities, offering hope for DKD. Interim analyses from our Phase I clinical trial delivering patient-derived MSC in non- diabetic renovascular disease demonstrated safety, preserved kidney function, and improved kidney blood flow. In experimental DKD, MSC decrease glomerulosclerosis, microalbuminuria, inflammation and fibrosis. We wish to test the potential of patient-derived MSC therapy to minimize the risk of allosensitization or cell destruction with allogeneic stem cell treatment approaches. However, MSC from individuals with DKD may function suboptimally due to senescence. Cellular senescence, an irreversible arrest of cell proliferation, is induced by DNA damage and promotes inflammation, contributing to tissue injury and cell dysfunction. In our Phase I randomized, open label trial, we are currently testing the safety and efficacy of senolytics, drugs that clear senescent cells, to repair the health of MSC in individuals with DKD. Preliminary studies show reductions in senescent adipose cells and improved MSC function. However, it remains unclear whether these changes affect MSC reparative capacity on injured renal cells or in DKD. Our long-term goal is to promote the development of a novel cell-based therapy for DKD. We hypothesize that senolytic agents taken by subjects with DKD will improve the renal repair capacity of the patient’s own MSC, by enhancing anti- inflammatory, anti-fibrotic and pro-angiogenic paracrine activities. Using adipose-derived MSCs harvested from subjects with advanced DKD (eGFR 15-45 ml/min/1.73m2) in the ongoing senolytic therapy trial, the proposed project will: (1) Test the hypothesis that DKD MSCs from subjects treated in vivo with senolytics (SenDKD-MSC) will achieve greater reduction in inflammation and epithelial-to-mesenchymal transition (EMT) program in injured renal tubule epithelial cells (TEC) in vitro, via paracrine-mediated actions, as compared to untreated DKD-MSC. (2) Test the hypothesis that SenDKD-MSC infusion will exhibit greater potency vs. DKD-MSC in the repair of mouse kidneys in vivo, by reducing albuminuria, fibrosis, hypoxia, and inflammation in experimental DKD with angiotensin II-induced hypertension. These pilot studies will allow the assessment of senolytic-induced MSC renal repair effects in experimental DKD and enhance successful testing of a novel, senolytic MSC preconditioning strategy in human DKD. Significance and Impact: Cell-based therapy to delay DKD progression is very promising. Senolytic therapy may improve stem cell function and multiple aging-related conditions. Unravelling the mechanisms by which these novel interventions may work to synergistically regenerate the diabetic kidney could lead to successful large-scale clinical trials in the future.

摘要 /项目摘要 糖尿病肾脏疾病（DKD）是肾脏疾病全球烧伤的主要驱动力，对大多数 治疗选择。这是至关重要的。 间充质基质细胞（MSC）批准治疗其他地方的难治性炎症性疾病 旁分泌抗纤维化，抗凋亡，促血管生成和免疫调节活性， 为DKD提供希望。从我们的I期临床试验中进行的临时分析，该试验提供了非患者衍生的MSC 糖尿病性肾血管疾病表现出安全性，保留的肾功能和改善的肾脏血液 流动。在实验性DKD中，MSC减少肾小球硬化，微量白蛋白尿，注射和纤维化。 我们希望测试患者衍生的MSC治疗的潜力，以最大程度地减少异敏或细胞的风险 具有同种异体干细胞处理方法的破坏。但是，来自DKD的人的硕士可能 由于感应而在次优的功能。细胞感应是细胞增殖的不可逆转，是 由DNA损伤诱导并促进感染，导致组织损伤和细胞功能障碍。在我们的 第一阶段的随机开放标签试验，我们目前正在测试塞溶剂的安全性和效率，药物，这些药物 清除感觉细胞，以修复DKD个体中MSC的健康。初步研究显示减少 在感觉脂肪细胞和改善MSC功能中。但是，尚不清楚这些是否发生了变化 影响MSC对受伤的肾细胞或DKD中的修复能力。我们的长期目标是促进 开发针对DKD的新型基于细胞的疗法。我们假设受试者采取的鼻溶剂 使用DKD将通过增强反抗 炎症，抗纤维化和促血管生成旁分泌活性。使用脂肪衍生的MSC 从正在进行的鼻溶治疗中的高级DKD（EGFR 15-45 ml/min/1.73m2）中收获 试验，拟议的项目将：（1）检验以下假设： Senolotics（SendKD-MSC）将使炎症和上皮到间质的降低更大 在体外受伤的肾小管上皮细胞（TEC）中的过渡（EMT）程序，通过旁分线介导的作用， 与未经处理的DKD-MSC相比。 （2）检验SendKD-MSC输注将退出更大的假设 通过减少蛋白尿，纤维化，缺氧和 血管紧张素II诱导的高血压的实验DKD炎症。这些试验研究将允许 评估实验DKD中鼻溶性诱导的MSC肾脏修复效应并增强成功 对人类DKD中新颖的鼻溶性MSC预处理策略的测试。意义和影响：基于细胞的 非常有望延迟DKD进展的治疗。塞溶性疗法可以改善干细胞功能，并且 多个与衰老有关的条件。阐明这些新颖干预措施可以起作用的机制 协同再生糖尿病性肾脏将来可能会成功进行大规模的临床试验。

项目成果

Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology.

• DOI: 10.34067/kid.0005692020
• 发表时间: 2021-03
• 期刊: Kidney360
• 作者: Hickson LJ;Herrmann SM;McNicholas BA;Griffin MD
• 通讯作者: Griffin MD

A systematic review and meta-analysis of cell-based interventions in experimental diabetic kidney disease.

• DOI: 10.1002/sctm.19-0419
• 发表时间: 2021-09
• 期刊: Stem cells translational medicine
• 影响因子: 6
• 作者: Hickson LJ;Abedalqader T;Ben-Bernard G;Mondy JM;Bian X;Conley SM;Zhu X;Herrmann SM;Kukla A;Lorenz EC;Kim SR;Thorsteinsdottir B;Lerman LO;Murad MH
• 通讯作者: Murad MH

Diabetic kidney disease induces transcriptome alterations associated with angiogenesis activity in human mesenchymal stromal cells.

• DOI: 10.1186/s13287-023-03269-9
• 发表时间: 2023-03-22
• 期刊: Stem cell research & therapy
• 影响因子: 7.5

Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells.

• DOI: 10.1002/jcp.29940
• 发表时间: 2021-03
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Kim SR;Zou X;Tang H;Puranik AS;Abumoawad AM;Zhu XY;Hickson LJ;Tchkonia T;Textor SC;Kirkland JL;Lerman LO
• 通讯作者: Lerman LO