Cyclo-oxygenase or TNF alpha inhibitors interferes with the enhanced mesenchymal stem cell homing induced by pulsed focused ultrasound: implication for regenerative medicine

Abstract

Recent studies have demonstrated the utility of noninvasive pulse focused ultrasound (pFUS) in enhanced homing permeability and retention (EHPR) of stem cells to targeted tissues (1). We show that pFUS targeted exposure to skeletal muscle (M) or kidney (K) results in nondestructive micro-environmental changes associated with increased expression cyclo-oxygenase (COX2) in tissues along with a cascade of cytokines, chemokines and trophic factors (CCTF) and cell adhesion molecules (CAM) initiating within 10 minutes and lasting up to 48 hours. pFUS induced a transient 4-6x increase in Tumor Necrosis Factor alpha (TNFa) within 10 minutes after exposure that returned to control levels of protein expression by 30 minutes. Following TNFa increases there was increases in both pro-inflammatory and anti-inflammatory factors (e.g., Interleukin (IL) 1, IL2, IL6, IL10, IL13, IL15, IL12p40, MCP-1, RANTES, VEGF, M-CSF, MIP-2, PDGF and FGF, EGF, TGFb) and CAM expressed in pFUS treated M or K. Coupling pFUS with IV of mesenchymal stem cells (MSC) after resulted in 5-8 times (ANOVA p<0.01) more of infused cells homing to M or K as compared to contralateral tissue. Pretreatment prior to pFUS with nonspecific COX inhibitor, ibuprofen (IB) or TNFa receptor binding protein, etanercept (ET), resulted in significant reduction in CCTF when compared results in pFUS only treated mice. Treatment with IB or ET prior to pFUS and IV MSCs resulted in significant (ANOVA p<0.05) reduction in homing to pFUS treated M or K similar to numbers of cells located in the contralateral tissue. pFUS exposure in COX2-/- knockout mice resulted in no differences in number of MSCs homing to treated tissue compared to contralateral control. pFUS induces a transient molecular zip code in treated tissue that can be used to evaluate drug-host interactions through interference of pathways and have an important impact on cell homing and therapy. 1. Ziadloo A, Stem Cells 2012;30:1216, Burks S, Stem Cells 2013;31:2551