Treating Kidney Injury by Modulating Heat Shock Proteins Using Soundwaves Combined with Mesenchymal Stem Cells and Their Extracellular Vesicles

声波结合间充质干细胞及其细胞外囊泡调节热休克蛋白治疗肾损伤

• 批准号: 10676146
• 负责人: Avnesh Sinh Thakor
• 金额: $ 51.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676146
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Animals; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Biodistribution; Cell Adhesion Molecules; Cell Proliferation; Cell Therapy; Cells; Chronic Kidney Failure; Cisplatin; Clinical; Custom; Development; Eligibility Determination; FDA approved; Fibrosis; Filtration; Focused Ultrasound; Heat shock proteins; Heat-Shock Proteins 70; Homing; Hospitalization; Human; Immune; In Vitro; Inflammasome; Inflammation; Injury; Injury to Kidney; Intervention; Intra-Arterial Infusions; Intra-Arterial Injections; Intravenous; Kidney; Kidney Failure; Left; Lung; Mechanical Stimulation; Mesenchymal Stem Cells; Molecular; Mus; Natural regeneration; Nature; Organ; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Physiologic pulse; Pre-Clinical Model; Proteomics; Proto-Oncogene Proteins c-akt; Regenerative capacity; Regenerative pathway; Renal function; Reproducibility; Reticuloendothelial System; Route; Source; Surface; Techniques; Technology; Testing; Tissues; Transducers; Vascular blood supply; Work; bone marrow mesenchymal stem cell; cell injury; clinical translation; cytokine; experimental study; extracellular vesicles; heat-shock proteins 20; hemodynamics; image guided; immunoregulation; improved; innovation; intravenous administration; minimally invasive; mouse model; new technology; paracrine; protective effect; radiologist; regenerative; release factor; renal damage; repaired; response; sound; stem cell therapy; tissue regeneration; transcriptome sequencing

PROJECT SUMMARY Acute kidney injury (AKI) is characterized by a rapid decline in kidney filtration, and if left untreated can lead to kidney failure. It is estimated there are 600,000 new cases of AKI each year, however, beyond careful medication selection and supportive hemodynamic optimization, there is currently no approved therapy. An innovative approach to halt, and possibly reverse, the progression of AKI is to use mesenchymal stem cell (MSC) based therapies. MSCs act as a “mobile drug store” to protect and regenerate damaged cells through anti-inflammatory, angiogenic, immunomodulatory, anti-fibrotic and anti-apoptotic factors, which are released either in a soluble form or within extracellular vesicles (EVs). In recent work, we have shown that both parent MSCs (i.e. a cellular therapy) and MSC-derived EVs (i.e. a cell-free therapy) can improve animal survival and kidney function following AKI, by modulating the heat shock protein (HSP) pathway. Although MSC based therapies have shown considerable promise in preclinical models of AKI, their clinical translation has been suboptimal. A major reason for this is that these therapies cannot reach the injured kidney when given to patients by conventional intravenous (IV) administration, with majority of parent MSCs getting trapped in the lungs and MSC-derived EVs getting trapped in the reticuloendothelial system (RES). Hence, we will examine if we can optimize MSC therapies by delivering them directly into the injured kidney by intra-arterial (IA) injection. We will also investigate the effect of a novel technology which uses sound waves, called pulsed focused ultrasound (pFUS), on both MSC therapies and the injured kidney given that it can (i) stimulate MSCs, (ii) modulate the kidney microenvironment by creating a “molecular zip-code to facilitate MSC homing and retention, and/or (iii) independently stimulate the HSP pathway to facilitate kidney regeneration. Focused ultrasound is an FDA-approved technology which is currently used clinically, albeit not for this indication. We will use a mouse model of AKI and GMP grade human bone marrow derived MSCs (BM-MSCs) from which we also derive EVs – given that MSC based therapies for all our experiments will be derived from a single source, this will allow for experimental reproducibility and enable our results to be compared across all our aims. In Aim 1, we will examine how sound waves affect BM-MSCs, as well as the acutely injured kidney, at a molecular level. In Aims 2 and 3, we will compare IV administration of either parent BM-MSCs or BM-MSC derived EVs, with locoregional IA administration directly into the kidneys - a technique developed by our Lab that mimics what Interventional Radiologists can perform in humans using minimally invasive image guided endovascular techniques. Next, we will determine how MSC based therapies modulate the molecular pathways involved in kidney regeneration, focusing specifically on HSPs. Finally, we will examine whether pFUS can optimize the regenerative capacity of MSC therapies in the context of AKI.

项目概要 急性肾损伤 (AKI) 的特点是肾脏滤过率迅速下降，如果不及时治疗可能会导致 然而，据估计每年有 600,000 例新发 AKI 病例。 药物选择和支持性血流动力学优化，目前尚无批准的治疗方法。 阻止并可能逆转 AKI 进展的创新方法是使用间充质干细胞 基于间充质干细胞（MSC）的疗法充当“移动药库”，通过保护和再生受损细胞。 释放抗炎、血管生成、免疫调节、抗纤维化和抗凋亡因子 在最近的工作中，我们已经证明，无论是在可溶形式还是在细胞外囊泡（EV）中。 MSC（即细胞疗法）和 MSC 衍生的 EV（即无细胞疗法）可以提高动物存活率和 AKI 后的肾功能，通过调节热休克蛋白 (HSP) 途径，尽管基于 MSC。 疗法在 AKI 的临床前模型中显示出相当大的前景，其临床转化已 造成这种情况的主要原因是这些疗法无法到达受伤的肾脏。 患者通过传统的静脉注射 (IV) 给药，大多数亲本 MSC 被困在 肺和 MSC 衍生的 EV 被困在网状内皮系统 (RES) 因此，我们将检查是否。 我们可以通过动脉内 (IA) 注射将 MSC 直接输送到受伤的肾脏中来优化 MSC 疗法。 我们还将研究一种使用声波的新技术的效果，称为脉冲聚焦 超声 (pFUS)，适用于 MSC 疗法和受损肾脏，因为它可以 (i) 刺激 MSC，(ii) 通过创建“分子邮政编码以促进 MSC 归巢和调节肾脏微环境” 保留，和/或 (iii) 独立刺激 HSP 途径以促进肾脏再生。 超声波是 FDA 批准的技术，目前在临床上使用，但不适用于此适应症。 将使用 AKI 和 GMP 级人骨髓衍生 MSC (BM-MSC) 的小鼠模型，我们从中获得 还衍生出 EV——考虑到我们所有实验的基于 MSC 的疗法都将来自单一来源， 这将实现实验的可重复性，并使我们的结果能够在我们的所有目标中进行比较。 目标 1，我们将检查声波如何影响 BM-MSC 以及急性损伤的肾脏， 在目标 2 和 3 中，我们将比较亲代 BM-MSC 或 BM-MSC 的 IV 给药。 衍生的 EV，将局部 IA 直接注射到肾脏中 - 这是我们实验室开发的技术 模仿介入放射科医生使用微创图像引导对人体进行的操作 接下来，我们将确定基于 MSC 的疗法如何调节分子途径。 参与肾脏再生，特别关注 HSP 最后，我们将检查 pFUS 是否可以。 优化 AKI 背景下 MSC 疗法的再生能力。

项目成果

Integrated transcriptome-proteome analyses of human stem cells reveal source-dependent differences in their regenerative signature.

人类干细胞的转录组-蛋白质组综合分析揭示了其再生特征的来源依赖性差异。

• 发表时间: 2023-01-10
• 影响因子: 5.9
• 作者: Ganguly, Abantika;Swaminathan, Ganesh;Garcia;Regmi, Shobha;Yarani, Reza;Primavera, Rosita;Chetty, Shashank;Bermudez, Abel;Pitteri, Sharon J;Thakor, Avnesh S
• 通讯作者: Thakor, Avnesh S