Kidney diseases contribute a significant morbidity and mortality burden on society. Progression of acute kidney injury (AKI) and chronic kidney disease (CKD) can ultimately result in end stage renal disease, for which dialysis and kidney transplantation are the only treatment options. In recent years, there has been a substantial increase in hospitalizations for AKI. However, there is no approved therapy for stopping, or even reversing, kidney damage with the standard approach being mostly supportive in nature.
A promising approach to treat AKI is to administer mesenchymal stem cell (MSC)-based therapies directly into the kidney. We have shown that both parent MSCs (i.e. a cellular therapy) and MSC-derived extracellular vesicles (EVs; i.e. a cell-free therapy) can improve the survival and function of damaged kidneys. While MSCs can recover kidney function, reduce inflammation and increase cellular proliferation in animal models of AKI1, MSC-derived EVs can decrease heat shock protein (HSP) 70, resulting in downregulation of the NLPRP3 inflammasome2. In addition, we have developed techniques to deliver MSC-based therapies directly into the injured kidney in small animal models, by intra-arterial (IA) injection– similar to what can be achieved using endovascular approaches by interventional radiologists1. This will avoid their first pass retention in the lungs and reticuloendothelial system following conventional intravenous infusion. Furthermore, we have shown that we can optimize the kidney microenvironment using a novel technology based on soundwaves called pulsed focused ultrasound (pFUS). Here, we observed that pFUS can upregulate HSP 20 and 40 in AKI, which results in activation of the P13K-AKT pathway; in turn, stimulating cellular proliferation while also decreasing apoptosis1,2,4.
- Ullah M, Liu DD, Rai S, Dadhania A, Jonnakuti S, Concepcion W, Thakor AS (2020). Reversing Acute Kidney Injury Using Pulsed Focused Ultrasound and MSC Therapy: A Role for HSP-Mediated PI3K/AKT Signaling. Molecular therapy. Methods & clinical development, 17, 683–694. PMID: 32346546; PMCID: PMC7177168.
- Ullah M, Liu DD, Rai S, Concepcion W, Thakor AS (2020). HSP70-Mediated NLRP3 Inflammasome Suppression Underlies Reversal of Acute Kidney Injury Following Extracellular Vesicle and Focused Ultrasound Combination Therapy. International journal of molecular sciences, 21, 4085. PMID: 32521623.
- Ng NN, Thakor AS (2020). Locoregional Delivery of Stem Cell-Based Therapies. Science Translational Medicine, 12(547). PMID: 32522806.
- Ullah M, Liu DD, Rai S, Razavi M, Choi J, Wang J, Concepcion W, Thakor AS (2020). A Novel Approach to Deliver Therapeutic Extracellular Vesicles Directly into the Mouse Kidney via Its Arterial Blood Supply. Cells, 9(4), 937. PMID: 32290286; PMCID: PMC7226986.