Enhancing homing permeability and retentions of stem cells (SC) to targeted tissues noninvasively by pulse focused ultrasound (PFUS): potential application in regenerative medicine

      Stem cells (SC) express surface integrins and home following intravenous injection by tethering to cell adhesion molecules (CAM) on activated endothelium followed by active transmigrating into the parenchyma in response to cytokine/chemokine and trophic factor (CCTF) gradients. However, cell homing to pathology is inefficient process with <5% of injected dose localizing to target. Pulse focused ultrasound (pFUS) is a therapeutic noninvasive technique that has been used for targeted tissue ablation or drug delivery for treatment of malignancy. pFUS treatment to tissues (i.e., muscle and kidney) induces a transient localized increased expression of CCTF and CAM on vascular surfaces presumably through mechanotransductive effect that can enhance homing permeability and retention (EHPR) of SC in vivo. Single or multiple daily pFUS exposures coupled with IV infusion of SC (i.e., bone marrow stromal cells, (BMSC) or CD34+CD133+ cells) EHPR in kidney or muscle in mice resulting in significant number of cells in targeted tissues compared to IV injection. Moreover, pFUS exposures result in transient significant increase in CAM on vascular surfaces in targeted areas compared to control. Mice administered Cisplatinum were treated with or without pFUS followed by IV BMSC revealed pFUS+BMSC-treated kidneys retained greater numbers of SCs compared to mice receiving BMSC alone. Furthermore, pFUS coupled with SC had greater protective effects significantly less disease activity on histology (necrosis and apoptosis) and rapid improvement in renal function (blood urea nitrogen and creatinine) recovery compared to BMSC alone 5 days after Cisplatinum administration. These results indicate that pFUS exposure increases expression of a complex local CCTF and CAMs (i.e., development of transient molecular zip code) in the tissue microenvironment that results in an EHPR targeted delivery of multiple SC types to target. Nondestructive pFUS modifies host tissue without altering cell product thereby creating a translatable approach for improving delivery of cellular therapies.
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