The synergistic effect of pulsed-focused ultrasound and umbilical cord mesenchymal stem cells in facilitating recovery from acute kidney injury through mitochondrial regulation and heat shock proteins

Acute Kidney Injury (AKI) remains a significant challenge with limited therapeutic interventions. This study explored the use of pulsed-focused ultrasound (pFUS) to prime the kidney, followed by mesenchymal stem cell (MSC) therapy to treat AKI. Our data showed that MSCs can mitigate some of the adverse effects of AKI, with these effects being greater with the use of umbilical cord (UC)-MSCs compared to bone marrow (BM)-MSCs. Next, we examined the effect of pFUS on the acutely injured kidney and found that compared to a single sonication, repeated sonication using pFUS at low acoustic doses (LpFUS) resulted in a substantial reduction in pro-inflammatory and immuno-modulatory cytokines. We then investigated the synergetic effect of repeated LpFUS followed by UC-MSC therapy; here, we found the therapeutic effects of UC-MSCs were enhanced resulting in a significant reduction in the blood urea nitrogen (BUN), improved body weight, and modulation of the kidney microenvironment with the expression of cytokines that created a more anti-inflammatory and regenerative milieu. Detailed transcriptomic analysis of acutely injured kidney tissue samples treated with LpFUS+UC-MSCs showed up-regulation of mitochondrial genes, specially PGC1α and DRP1, mitochondrial-associated proteins involved in the respiratory chain, nuclear genes encoding mitochondrial proteins, mitochondrial function, and specific heat shock proteins (i.e., HSP70 and HSP90). In conclusion, our results show that the therapeutic effect of UC-MSCs for treating AKI can be augmented by priming the kidney with repeated LpFUS before UC-MSC therapy. This innovative approach holds promise for advancing the treatment of AKI.