Tebebi Pamela A, Burks Scott R, Kim Saejeong J, Williams Rashida A, Nguyen Ben A, Venkatesh Priyanka, Frenkel Victor, Frank Joseph A
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.
Stem Cells. 2015 Apr;33(4):1173-86. doi: 10.1002/stem.1927.
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.
对于再生医学而言，使注入的干细胞最大限度地归巢至患病组织至关重要。脉冲聚焦超声（pFUS）是一个可用于引导干细胞迁移的临床相关平台。通过机械转导，pFUS在经处理的骨骼肌中建立细胞因子、趋化因子、营养因子（CCTF）和细胞黏附分子（CAM）的局部梯度，随后注入的间充质基质细胞（MSC）可利用这些梯度迁移至实质组织。对机械性pFUS效应的分子反应进行表征发现，肿瘤坏死因子-α（TNFα）驱动环氧合酶-2（COX2）信号传导，以局部增加MSC归巢所必需的CCTF/CAM。在用布洛芬（非特异性COX抑制剂）或依那西普（TNFα抑制剂）预处理的小鼠中，pFUS未能增加趋化因子并诱导MSC归巢至经处理的肌肉。在COX2基因敲除小鼠中，pFUS诱导的MSC归巢也受到抑制，这表明布洛芬通过作用于COX2阻断了机械诱导的CCTF/CAM。包括布洛芬在内的抗炎药物会给予肌肉萎缩症（MD）患者，并且在MD小鼠模型中，布洛芬也抑制了pFUS诱导的向肌肉的归巢。药物与细胞疗法之间的相互作用尚未得到探索，并且在临床细胞疗法试验中也未得到控制。本研究强调了可能存在的负面药物-宿主相互作用，这些相互作用会抑制干细胞归巢，并可能破坏基于细胞的再生医学方法。
