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

点击翻译按钮获取中文摘要

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.