Abstract
BackgroundAcute kidney injury (AKI) is characterized by rapid failure of renal function and has no curative therapies. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are known to carry therapeutic factors, which have shown promise in regenerative medicine applications, including AKI. However, there remains an unmet need to optimize their therapeutic effect. One potential avenue of optimization lies in pulsed focused ultrasound (pFUS), where tissues-of-interest are treated with sound waves. pFUS has been shown to enhance MSC therapy via increased cell homing, but its effects on cell-free EV therapy remain largely unexplored.MethodsWe combine pFUS pretreatment of the kidney with MSC-derived EV therapy in a mouse model of cisplatin-induced AKI.ResultsEVs significantly improved kidney function, reduced injury markers, mediated increased proliferation, and reduced inflammation and apoptosis. While pFUS did not enhance EV homing to the kidney, the combined treatment resulted in a superior therapeutic effect compared to either treatment alone. We identified several molecular mechanisms underlying this synergistic therapeutic effect, including upregulation of proliferative signaling (MAPK/ERK, PI3K/Akt) and regenerative pathways (eNOS, SIRT3), as well as suppression of inflammation.ConclusionTaken together, pFUS may be a strategy for enhancing the therapeutic efficacy of MSC-derived EV treatment for the treatment of AKI.
Highlights
Acute kidney injury (AKI) is characterized by rapid failure of renal function and has no curative therapies
Extracellular vesicle (EV) and pulsed focused ultrasound (pFUS) reduce the clinical manifestations of AKI EVs were confirmed to be positive for the expression of CD9, CD63, and TSG101, with quantification normalized to the internal control CD81 (CD9: 5.77 ± 1.34 relative expression; CD63: 2.25 ± 1.66 relative expression; TSG101: 8.64 ± 6.10 relative expression) (Fig. 1a)
Animals treated with EVs alone or pFUS + EVs showed no mortality at day 12
Summary
Acute kidney injury (AKI) is characterized by rapid failure of renal function and has no curative therapies. PFUS has been shown to enhance MSC therapy via increased cell homing, but its effects on cell-free EV therapy remain largely unexplored. Acute kidney injury (AKI) is a condition characterized by a rapid deterioration of kidney function and is a common problem in hospitalized patients as well as those with comorbid chronic diseases [1]. Ullah et al Stem Cell Research & Therapy (2020) 11:398 studies have shown that AKI may initiate the development of chronic kidney disease (CKD) or, where CKD is already present, accelerate its worsening [5,6,7,8,9,10]. There is an urgent need for new therapies that might repair injured kidneys and prevent the progression to worsening kidney disease
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