Reversing Acute Kidney Injury Using Pulsed Focused Ultrasound and MSC Therapy: A Role for HSP-Mediated PI3K/AKT Signaling

Pulsed focused ultrasound enhances the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles in acute kidney injury

“…In AKI, they found that pFUS alone did not significantly improve kidney function (creatinine and BUN), promote cell proliferation (Ki67 and p-Akt), or reduce apoptosis and necrosis. However, pFUS alone did elicit these effects in our current and previous experiments [29,42]. This discrepancy may result from different ultrasound transducers and settings; given that there is a lack of data on how the biological effects of pFUS are influenced by specific ultrasound parameters, direct comparison between studies is difficult.…”

“…Consistent with these findings, a previous study has shown that ultrasound can prevent AKI by stimulating cholinergic anti-inflammatory pathways [58], though that study used unfocused ultrasound. These effects of pFUS alone were observed in some previous studies [29,42], but not others [30], which may be an effect of different ultrasound parameters. It is also possible that there may be some sensitization effect, wherein pFUS sensitizes the target tissue to the regenerative molecules carried by EVs, thereby increasing their therapeutic efficacy; this hypothesis, though exciting, requires further exploration.…”

“…In the setting of a mouse model of cisplatin-induced AKI, this increased homing of MSCs after pFUS was able to improve renal function more so than MSCs alone [30]. However, we have previously demonstrated that pFUS can enhance MSC therapy without local upregulation of cytokines or increased MSC homing [29]. Instead, pFUS was shown to act through protein intermediates to spur endogenous proliferation pathways, an effect which synergized with MSCs.…”

“…When combined with imaging guidance, pFUS can be targeted precisely to locations deep within the body. Previous studies have shown that pFUS can enhance MSC therapy for AKI [ 29 , 30 ], but different mechanisms have been proposed for this effect. The homing hypothesis posits that sound waves transiently upregulate local inflammatory and chemoattractive signals [ 31 – 33 ].…”

“…The homing hypothesis posits that sound waves transiently upregulate local inflammatory and chemoattractive signals [ 31 – 33 ]. This local gradient of cytokines, chemokines, and trophic factors has been shown to promote the homing of MSCs to various tissues including the skeletal muscle [ 34 , 35 ] and the kidney [ 29 , 30 , 32 , 36 ]. In the setting of a mouse model of cisplatin-induced AKI, this increased homing of MSCs after pFUS was able to improve renal function more so than MSCs alone [ 30 ].…”