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

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)是慢性肾脏病(CKD)抵抗的第二大原因 有效的干预措施，防止病情恶化。然而，再生医学的最新进展与使用 脂肪组织来源的间充质干细胞(AD-MSC)移植为这些提供了希望 病人。骨髓间充质干细胞具有抗纤维化、抗炎和促进血管生成的旁分泌活性，可以改善 某些肾损伤模型中的再生。然而，暴露于特定于患者的因素，如衰老和 HN中CKD的尿毒症环境可能对MSC实施表观遗传和转录调控，可能是潜在的 将它们的表型修改为对邻近细胞有害的表型。因此，HN细胞损伤增加可能 实质上损害了MSC的功能，并成为成功进行自体MSC移植的障碍。 我们支持这一建议的中心假设是，从HN患者获得的MSCs显示受损 功能和血管生成，这可以用低氧预适应(HPC)来改变。这一假说将 在体外和体内都有三个特定的目标：1)我们将比较来自 年龄和性别匹配的高血压患者的HN(EGFR 15-60mL/min/1.73m2)到MSC 和健康对照组；2)为了确定HN-MSC功能障碍的可逆性，我们将这些细胞 3)检测MSC在体外对HPC功能的影响。 体内，我们将在猪肾血管性高血压模型中进行实验研究 肾动脉狭窄诱导6周后HN的病理生理变化。这些猪，以及正常的 年龄匹配的猪将接受HPC-MSC、未处理的MSC或赋形剂处理。评估高性能混凝土对以下方面的影响 MSC的效力、肾脏血流动力学、功能和氧合作用将在四周后进行研究，使用 先进的体内CT和MR成像技术，以及体外研究的肾脏损伤和血管。这个 拟议研究的意义很高，因为开发了一种安全有效的疗法来延缓HN 进展可以减少与透析相关的发病率，为人群提供更好的治疗选择 通常推迟到肾脏移植，并产生广泛的成本节约。这些新奇的研究将 提高对HPC对MSC的影响及其有害微环境的认识，帮助 开发一种全新的治疗策略来延缓支持NIDDK的HN的进展 任务。拟议的项目解决了如何表征和改进MSC的功能特性 HN允许这些患者从未来使用干细胞移植的临床试验中受益。这个 梅奥诊所的特殊资源和机构支持，杰出的多学科指导团队， 拟议的职业发展活动将使应聘者实现她成为 他是一名独立的研究人员，也是国家公认的肾脏再生医学领域的领导者。

项目成果

The 'other' big complication: how chronic kidney disease impacts on cancer risks and outcomes.

“另一个”大并发症：慢性肾病如何影响癌症风险和结果。

• DOI: 10.1093/ndt/gfac011
• 发表时间: 2023-05-04
• 期刊: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

Renal ischemia alters the transcriptomic and epigenetic profile of inflammatory genes in swine scattered tubular-like cells.

• DOI: 10.1042/cs20230555
• 发表时间: 2023-08-31
• 期刊: Clinical science (London, England : 1979)

Hypertension and Prohypertensive Antineoplastic Therapies in Cancer Patients.

• DOI: 10.1161/circresaha.121.318051
• 发表时间: 2021-04-02
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: van Dorst DCH;Dobbin SJH;Neves KB;Herrmann J;Herrmann SM;Versmissen J;Mathijssen RHJ;Danser AHJ;Lang NN
• 通讯作者: Lang NN

Incidence and Risk Factors for Acute Kidney Injury After Chimeric Antigen Receptor T-Cell Therapy.

嵌合抗原受体T细胞治疗后急性肾损伤的发生率和危险因素。

• DOI: 10.1016/j.mayocp.2022.05.018
• 发表时间: 2022-07
• 期刊: MAYO CLINIC PROCEEDINGS
• 影响因子: 8.9
• 作者: Farooqui, Naba;Sy-Go, Janina Paula T.;Miao, Jing;Mehta, Ramila;Vaughan, Lisa E.;Bennani, N. Nora;Wang, Yucai;Bansal, Radhika;Hathcock, Matthew A.;Hayman, Suzanne R.;Johnston, Patrick B.;Villasboas, Jose C.;Paludo, Jonas;Ansell, Stephen M.;Leung, Nelson;Lin, Yi;Herrmann, Sandra M.
• 通讯作者: Herrmann, Sandra M.

Renal Revascularization Attenuates Myocardial Mitochondrial Damage and Improves Diastolic Function in Pigs with Metabolic Syndrome and Renovascular Hypertension.

肾脏血运重建会减弱心肌线粒体损伤，并改善代谢综合征和肾血管高血压的猪的舒张功能。

• DOI: 10.1007/s12265-021-10155-3
• 发表时间: 2022-03
• 期刊: Journal of cardiovascular translational research
• 影响因子: 3.4
• 作者: Farahani RA;Yu S;Ferguson CM;Zhu XY;Tang H;Jordan KL;Saadiq IM;Herrmann SM;Chade AR;Lerman A;Lerman LO;Eirin A
• 通讯作者: Eirin A