title: Cyclooxygenase-2 or tumor necrosis factor-α inhibitors attenuate the mechanotransductive effects of pulsed focused ultrasound to suppress mesenchymal stromal cell homing to healthy and dystrophic muscle.
abstract: Maximal homing of infused stem cells to diseased tissue is critical for regenerative medicine. Pulsed focused ultrasound (pFUS) is a clinically relevant platform to direct stem cell migration. Through mechanotransduction, pFUS establishes local gradients of cytokines, chemokines, trophic factors (CCTF) and cell adhesion molecules (CAM) in treated skeletal muscle that subsequently infused mesenchymal stromal cells (MSC) can capitalize to migrate into the parenchyma. Characterizing molecular responses to mechanical pFUS effects revealed tumor necrosis factor-alpha (TNFα) drives cyclooxygenase-2 (COX2) signaling to locally increase CCTF/CAM that are necessary for MSC homing. pFUS failed to increase chemoattractants and induce MSC homing to treated muscle in mice pretreated with ibuprofen (nonspecific COX inhibitor) or etanercept (TNFα inhibitor). pFUS-induced MSC homing was also suppressed in COX2-knockout mice, demonstrating ibuprofen blocked the mechanically induced CCTF/CAM by acting on COX2. Anti-inflammatory drugs, including ibuprofen, are administered to muscular dystrophy (MD) patients, and ibuprofen also suppressed pFUS-induced homing to muscle in a mouse model of MD. Drug interactions with cell therapies remain unexplored and are not controlled for during clinical cell therapy trials. This study highlights potentially negative drug-host interactions that suppress stem cell homing and could undermine cell-based approaches for regenerative medicine.
authors.affiliation: Department of Biomedical Engineering, Catholic University of America, Washington, District of Columbia, USA; Frank Lab, Radiology and Imaging Sciences Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Tebebi
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burks
authors.forename: Saejeong J
authors.initials: SJ
authors.lastname: Kim
authors.forename: Rashida A
authors.initials: RA
authors.lastname: Williams
authors.forename: Ben A
authors.initials: BA
authors.lastname: Nguyen
authors.forename: Priyanka
authors.initials: P
authors.lastname: Venkatesh
authors.forename: Victor
authors.initials: V
authors.lastname: Frenkel
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Frank
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D057507:Mice, 129 Strain; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009136:Muscular Dystrophies / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000069453:Ultrasonic Waves; D055815:Young Adult
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D014409:Tumor Necrosis Factor-alpha
keywords: Cell adhesion molecules; Cyclooxygenase-2; Cytokines; Etanercept; Focused ultrasound; Ibuprofen; MDX; Mechanotransduction; Mesenchymal stromal cell, Mesenchymal stem cell, Cell homing; Nuclear factor kappa-light-chain-enhancer of activated B cells; Tumor necrosis factor alpha; muscle; muscular dystrophy