Bone marrow stromal cells (BMSCs) 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 muscle and kidney following pFUS has little effect on the histological integrity of the tissue and does not induce cell death. pFUS increased expression of several chemoattractants creating a transient molecular zip code on days 0 and 1 following pFUS that returns to baseline levels by day 3 post-pFUS. pFUS exposures induced up-regulation of cell adhesion molecules on muscle vasculature. The observed molecular changes in muscle following pFUS may be utilized to target cellular therapies, by increasing homing to areas of pathology. We induce a mechanotransductive response that initiates a largely an anti-inflammatory M2-type macrophage environment. We demonstrated local upregulation of chemoattractants in pFUS-treated skeletal muscle and kidney leads to enhance homing, permeability, and retention of BMSC or human endothelial precursor cells (EPC). Furthermore, the magnitude of BMSC or EPC homing was increased when pFUS treatments and cell infusions were repeated daily in muscle. We also demonstrate that the induced molecular changes following pFUS to muscle and kidney can be block by ibuprofen, a cyclooxygenase 2 inhibitor, or TNF alpha receptor binding protein, etanercept, indicating that the mechanotransductive effects are acting through a NFkB and COX 2 pathway in the tissue. Both ibuprofen or etanercept administered prior to pFUS and stem cell infusion block the homing of stem cells to targeted muscle which indicated that using this approach we can use pFUS to interrogate drug-host tissue interactions and their effect on homing. We also 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+BMSC 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+BMSC. BMSCs, 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 BMSC that home to the tissue. pFUS coupled with BMSCs enhances cellular therapy to prevent AKI and allows rescue therapy in established AKI, which currently has no meaningful therapeutic options. We also have similar results in critical limb ischemia model in which we have been able to demonstrate that the combination of pFUS+BMSC resulted in greater reperfusion of the ischemic limb compared to animal receiving pFUS or BMSC alone. Evaluation of the tissue demonstrated pFUS pretreatment followed by BMSC infusion of the ischemic muscle increased the amount of human vascular endothelia growth factor and interleukin 10 present in the microenvironment compared to animals only receiving BMSC injections. These results indicate that pFUS preconditions the tissues that results in increased potency of the BMSC that homed to targeted tissues and has important implication for translation to clinical trials.

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Kovacs, Zsofia I; Burks, Scott R; Frank, Joseph A (2018) Focused ultrasound with microbubbles induces sterile inflammatory response proportional to the blood brain barrier opening: Attention to experimental conditions. Theranostics 8:2245-2248
Jang, Kee W; Seol, Dongrim; Ding, Lei et al. (2018) Ultrasound-Mediated Microbubble Destruction Suppresses Melanoma Tumor Growth. Ultrasound Med Biol 44:831-839
Burks, Scott R; Nguyen, Ben A; Bresler, Michele N et al. (2017) Anti-inflammatory drugs suppress ultrasound-mediated mesenchymal stromal cell tropism to kidneys. Sci Rep 7:8607
Kovacs, Zsofia I; Kim, Saejeong; Jikaria, Neekita et al. (2017) Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci U S A 114:E75-E84
Kovacs, Zsofia I; Burks, Scott R; Frank, Joseph A (2017) Reply to Silburt et al.: Concerning sterile inflammation following focused ultrasound and microbubbles in the brain. Proc Natl Acad Sci U S A :
Jang, Kee W; Tu, Tsang-Wei; Nagle, Matthew E et al. (2017) Molecular and histological effects of MR-guided pulsed focused ultrasound to the rat heart. J Transl Med 15:252
Tebebi, Pamela A; Kim, Saejeong J; Williams, Rashida A et al. (2017) Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound. Sci Rep 7:41550
Burks, Scott R; Nguyen, Ben A; Tebebi, Pamela A et al. (2015) Pulsed focused ultrasound pretreatment improves mesenchymal stromal cell efficacy in preventing and rescuing established acute kidney injury in mice. Stem Cells 33:1241-53
Tebebi, Pamela A; Burks, Scott R; Kim, Saejeong J et al. (2015) Cyclooxygenase-2 or tumor necrosis factor-? inhibitors attenuate the mechanotransductive effects of pulsed focused ultrasound to suppress mesenchymal stromal cell homing to healthy and dystrophic muscle. Stem Cells 33:1173-86
Burks, Scott R; Ziadloo, Ali; Kim, Saejeong J et al. (2013) Noninvasive pulsed focused ultrasound allows spatiotemporal control of targeted homing for multiple stem cell types in murine skeletal muscle and the magnitude of cell homing can be increased through repeated applications. Stem Cells 31:2551-60

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