Bone marrow stromal cells (BMSCs) or mesenchymal stem cells (MSC) have shown significant promise in the treatment of disease, but their therapeutic efficacy is often limited by inefficient homing of systemically administered cells, which results in low number of cells accumulating at sites of pathology. BMSC home to areas of inflammation where local expression of cell adhesion molecules and chemokine gradients are present. Pulsed focused ultrasound (pFUS) employs non-continuous exposures, that lower the rate of energy deposition and allow cooling to occur between pulses, thereby minimizing thermal effects and emphasizing the effects created by non-thermal mechanisms of FUS (i.e. acoustic radiation forces and acoustic cavitation). We examined changes in the kidney following pFUS has little effect on the histological integrity of the tissue and does not induce cell death. We demonstrated that pFUS exposures in combination with BMSC in an acute kidney injury model induce mechanotransductive effects in the murine kidney (AKI). To examine the efficacy of pFUS-enhanced cell homing in disease, we targeted pFUS to kidneys to enhance BMSC homing after cisplatin-induced AKI. We found that pFUS enhanced BMSC homing at 1 day post-cisplatin, prior to renal functional deficits, and that enhanced homing improved outcomes of renal function, tubular cell death, and regeneration at 5 days post-cisplatin compared to BMSCs alone. After observing improved homing and AKI outcomes during early AKI, we investigated whether pFUS+MSC therapy could rescue established AKI. BMSC administration alone at 3 days post-cisplatin, after renal functional deficits become obvious, significantly improved 7-day survival of animals. Survival was further improved using pFUS+MSC. MSCs, alone or with pFUS, shifted the kidney macrophage phenotype from M1 to M2. This study shows that pFUS serves as a neoadjuvant treatment to improve MSC homing to diseased organs. We have also shown that pFUS increases interferon gamma in tissue that augments the local potency of the infused MSC that home to the tissue by stimulating release of interleukin (IL) 10 from infused cells. We also established that pFUS induces an interferon gamma and IL 10 interaction in renal injury. We were able to demonstrate that silencing IL 10 in infused MSC results in worsening of renal injury following pFUS. These results indicate that pFUS preconditions the tissues that results in increased potency of the MSC that homed to targeted tissues and has important implication for translation to clinical trials. We also developed a noninvasive model of cardiac/chest contusion with pFUS to the left ventricle that resulted in a sterile inflammatory response in the myocardium along with pulmonary hemorrhage. Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized bloodbrain barrier (BBB) disruption as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and tumor necrosis factor indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected that lasted 24 h. The effect of pFUS+MB was due to an intravascular pressure wave from stable cavitation of the MB and resulted in TUNEL+ neurons, activated microglia and astrocytes and an innate immune response that would be compatible with mild trauma or ischemia in the brain. Six weekly courses of pFUS+MB in the brain can cause increases in hyperphosphorylated Tau in neurons as well as cortical atrophy.
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