Hypoxic preconditioning for the improvement of the regenerative capacity of adipose-derived mesenchymal stem cells and its application in chronic kidney disease due to hypertensive nephropathy

低氧预处理提高脂肪间充质干细胞再生能力及其在高血压肾病慢性肾脏病中的应用

• 批准号: 10412981
• 负责人: Sandra M Herrmann
• 金额: $ 15.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412981
• 关键词: Address; Adipose tissue; Affect; Age; Aging; Angiogenic Factor; Anti-Inflammatory Agents; Architecture; Attenuated; Autologous; Biological Assay; Cell physiology; Cells; Chronic Kidney Failure; Clinic; Clinical Trials; Cost Savings; Data; Dialysis procedure; Disease Resistance; EGF gene; End stage renal failure; Endothelial Cells; Enrollment; Epigenetic Process; Exposure to; Family suidae; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Goals; Histone Acetylation; Human; Hypertension; Hypoxia; Imaging Techniques; Impairment; In Vitro; Injury to Kidney; Investigational New Drug Application; Kidney; Kidney Transplantation; Knowledge; Magnetic Resonance Imaging; Mediator of activation protein; Mentorship; Mesenchymal; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methods; MicroRNAs; Microcirculation; Mission; Modeling; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Nephrology; Oxygen; Patients; Persons; Phenotype; Population; Property; Proteins; Public Health; Regenerative Medicine; Regenerative capacity; Renal Artery Stenosis; Renal Hypertension; Renal function; Renovascular Hypertension; Research Personnel; Resources; Risk Factors; Stem cell transplant; Structure; Testing; Therapeutic; Time; Toxin; Tube; Umbilical vein; Vascular Endothelial Growth Factors; X-Ray Computed Tomography; angiogenesis; base; blood oxygen level dependent; cardiovascular risk factor; career development; cell age; cell injury; cohort; detector; disorder risk; effective intervention; effective therapy; experimental study; extracellular vesicles; hemodynamics; human adult stem cell; human stem cells; human subject; hypertensive; improved; in vivo; injury and repair; kidney dysfunction; kidney repair; kidney vascular structure; microCT; migration; mortality; multidisciplinary; non-diabetic; novel; novel strategies; novel therapeutic intervention; paracrine; porcine model; preclinical study; preconditioning; prevent; protein expression; regenerative cell; regenerative therapy; renal artery; repaired; sex; stem cell function; stem cells; therapeutically effective; tissue injury; transcriptome sequencing; vesicular release; Address; Adipose tissue; Affect; Age; Aging; Angiogenic Factor; Anti-Inflammatory Agents; Architecture; Attenuated; Autologous; Biological Assay; Cell physiology; Cells; Chronic Kidney Failure; Clinic; Clinical Trials; Cost Savings; Data; Dialysis procedure; Disease Resistance; EGF gene; End stage renal failure; Endothelial Cells; Enrollment; Epigenetic Process; Exposure to; Family suidae; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Goals; Histone Acetylation; Human; Hypertension; Hypoxia; Imaging Techniques; Impairment; In Vitro; Injury to Kidney; Investigational New Drug Application; Kidney; Kidney Transplantation; Knowledge; Magnetic Resonance Imaging; Mediator of activation protein; Mentorship; Mesenchymal; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methods; MicroRNAs; Microcirculation; Mission; Modeling; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Nephrology; Oxygen; Patients; Persons; Phenotype; Population; Property; Proteins; Public Health; Regenerative Medicine; Regenerative capacity; Renal Artery Stenosis; Renal Hypertension; Renal function; Renovascular Hypertension; Research Personnel; Resources; Risk Factors; Stem cell transplant; Structure; Testing; Therapeutic; Time; Toxin; Tube; Umbilical vein; Vascular Endothelial Growth Factors; X-Ray Computed Tomography; angiogenesis; base; blood oxygen level dependent; cardiovascular risk factor; career development; cell age; cell injury; cohort; detector; disorder risk; effective intervention; effective therapy; experimental study; extracellular vesicles; hemodynamics; human adult stem cell; human stem cells; human subject; hypertensive; improved; in vivo; injury and repair; kidney dysfunction; kidney repair; kidney vascular structure; microCT; migration; mortality; multidisciplinary; non-diabetic; novel; novel strategies; novel therapeutic intervention; paracrine; porcine model; preclinical study; preconditioning; prevent; protein expression; regenerative cell; regenerative therapy; renal artery; repaired; sex; stem cell function; stem cells; therapeutically effective; tissue injury; transcriptome sequencing; vesicular release

PROJECT SUMMARY/ABSTRACT Hypertensive Nephropathy (HN) is the second leading cause of chronic kidney disease (CKD) resistant to effective intervention to prevent progression. However, recent advances in regenerative medicine with the use of adipose tissue-derived mesenchymal stromal/stem cell (AD-MSC) transplantation offer hope for these patients. The MSCs have anti-fibrotic, anti-inflammatory, and pro-angiogenic paracrine activities that improve regeneration in some kidney injury models. However, exposure to patient-specific factors, such as aging and the uremic milieu of CKD in HN, may exert epigenetic and transcriptional modulation of MSC, potentially modifying their phenotype to one noxious to neighboring cells. Hence, increased cellular damage in HN may substantially compromise MSC function and become a barrier to successful autologous MSC transplantation. Our central hypothesis underlying this proposal is that MSCs obtained from patients with HN show impaired functionality and angiogenesis, which can be modified with hypoxic preconditioning (HPC). This hypothesis will be addressed both in vitro and in vivo in three specific aims: 1) we will compare functionality of MSCs from patients with HN (eGFR 15-60 mL/min/1.73m2) to MSC from age- and sex-matched patients with hypertension and healthy controls; 2) to determine the reversibility of HN-MSC dysfunction, we will subject cells from these cohorts to HPC in vitro and assess MSC function thereafter; and 3) to examine the effect of MSC function in vivo, we will conduct an experimental study in a porcine renovascular hypertension model that recapitulates the pathophysiology of HN, six-weeks after induction of renal artery stenosis. These pigs, as well as normal age-matched pigs, will be treated with HPC-MSC, untreated-MSC, or vehicle. To assess the impact of HPC on MSC potency, renal hemodynamics, function, and oxygenation will be studied after four-weeks, using sophisticated in vivo CT and MR imaging techniques, and renal injury and vascularity studied ex vivo. The significance of the proposed studies is high, since developing a safe and effective therapy to delay HN progression could reduce morbidity associated with dialysis, offer a better treatment option to a population often deferred for kidney transplantation, and produce extensive cost savings. These novel studies will advance the knowledge of the effects of HPC on MSC and their deleterious microenvironment, aid in developing a completely novel therapeutic strategy to delay the progression of HN supporting the NIDDK mission. The proposed project addresses how characterize and improve the functional properties of MSC in HN to allow these patients to benefit from future enrollment in clinical trials using stem cell transplantation. The exceptional resources and institutional support at Mayo Clinic, outstanding multi-disciplinary mentorship team, and proposed career development activities will allow the candidate to achieve her long-term goal of becoming an independent investigator and a nationally recognized leader in regenerative medicine in nephrology.

项目摘要/摘要 高血压肾病（HN）是抗慢性肾脏疾病（CKD）的第二大原因 有效的干预以防止进展。但是，使用的最新再生医学进展 脂肪组织衍生的间充质基质/干细胞（AD-MSC）移植为这些带来希望 患者。 MSC具有抗纤维化，抗炎和促血管生成旁分泌活性，可改善 一些肾脏损伤模型的再生。但是，暴露于患者特异性因素，例如衰老和 HN中CKD的尿毒症环境可能会发挥MSC的表观遗传和转录调节 将其表型修改为一个对相邻细胞的有害细胞。因此，HN的细胞损伤增加了 基本上损害了MSC功能，并成为成功自体MSC移植的障碍。 我们的中心假设是该提案是从HN患者获得的MSC显示出受损 功能和血管生成，可以通过缺氧预处理（HPC）修饰。这个假设将会 在三个特定目标中都可以在体外和体内解决：1）我们将比较MSC的功能 患有高血压年龄和性别匹配的患者的HN患者（EGFR 15-60 mL/min/1.73m2）至MSC 和健康的对照； 2）确定HN-MSC功能障碍的可逆性，我们将受到这些细胞的影响 在体外与HPC队列并评估MSC功能； 3）检查MSC功能在 Vivo，我们将在猪的肾血管高血压模型中进行一项实验研究，该模型概括 HN的病理生理，肾动脉狭窄诱导后的六周。这些猪以及正常 年龄匹配的猪将用HPC-MSC，未经处理的MSC或车辆治疗。评估HPC对 MSC效力，肾脏动力学，功能和氧合将在四个周后研究，使用 在体内和MR成像技术中进行了复杂的研究，肾脏损伤和血管性研究了。这 拟议研究的重要性很高，因为开发了一种安全有效的疗法来延迟HN 进展可以降低与透析相关的发病率，为人群提供更好的治疗选择 通常会推迟用于肾脏移植，并节省大量成本。这些新研究将 促进HPC对MSC及其有害微环境的影响的了解，有助于 制定一种完全新颖的治疗策略，以延迟支持NIDDK的HN的发展 使命。所提出的项目解决了如何表征和改善MSC在 HN可以使这些患者使用干细胞移植中的临床试验中的未来入学人数受益。这 杰出的多学科指导团队梅奥诊所的卓越资源和机构支持， 拟议的职业发展活动将使候选人能够实现她的长期目标 独立研究者和全国认可的肾脏病再生医学领导者。