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 (non-specific 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.

Mechanical Stretching Promotes Skin Tissue Regeneration via Enhancing Mesenchymal Stem Cell Homing and Transdifferentiation

“…The homing of infused MSCs to the target site is crucial in regenerative medicine [21]. In the present study, SDF‐1α was expressed in the basal layer of the epidermis and the outer root sheath of hair follicles after mechanical stretching.…”

Mesenchymal stromal cell potency to treat acute kidney injury increased by ultrasound‐activated interferon‐γ/interleukin‐10 axis

“…We have extensively investigated the molecular effects of pFUS and employed pFUS to improve MSC tropism and outcomes in several disease models . When MSCs are not stimulated by the pFUS‐altered renal microenvironment (ie.…”

“…shockwaves) into the parenchyma. The pFUS sonications described here have been applied to renal and muscle tissue without significant cellular damage—a likely necessity for regenerative medicine approaches . Interestingly, it has been reported that diagnostic ultrasound to the spleen stimulates cholinergic anti‐inflammatory pathways through haematopoietic nicotinic acetylcholine receptors to reduce inflammation and improve the specific duration of ischaemic reperfusion induced AKI …”

“…We have used pulsed focused ultrasound (pFUS) to increase homing of intravenous (i.v. )‐injected MSC to desired locations and shown associations with improved pathology . Image‐guided FUS is a noninvasive modality which is a clinically approved treatment for thermal ablation of patients with essential tremor, uterine fibroids and prostate cancer .…”

“…)-injected MSC to desired locations and shown associations with improved pathology. [17][18][19][20][21][22] Image-guided FUS is a noninvasive modality which is a clinically approved treatment for thermal ablation of patients with essential tremor, uterine fibroids and prostate cancer. [23][24][25] pFUS minimizes heating and allows acoustic mechanical effects to predominate.…”