Noninvasive pulsed focused ultrasound allows spatiotemporal control of targeted homing for multiple stem cell types in murine skeletal muscle and the magnitude of cell homing can be increased through repeated applications

Authors

  • Scott R. Burks,

    Corresponding author
    1. Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA
    2. Imaging Sciences Training Program, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA
    • Correspondence: Scott R. Burks, Ph.D., 10 Center Drive, Room B1N256, Bethesda, Maryland 20892, USA. Telephone: +1-301-594-2368; Fax: +1-301-402-3216; e-mail: scott.burks@nih.gov

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    • Author contributions: S.R.B.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; A.Z. and S.J.K.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; B.A.N.: collection and/or assembly of data and final approval of manuscript; J.A.F.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  • Ali Ziadloo,

    1. Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA
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  • Saejeong J. Kim,

    1. Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA
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  • Ben A. Nguyen,

    1. Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA
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  • Joseph A. Frank

    1. Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA
    2. Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, Bethesda, Maryland, USA
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Abstract

Stem cells are promising therapeutics for cardiovascular diseases, and i.v. injection is the most desirable route of administration clinically. Subsequent homing of exogenous stem cells to pathological loci is frequently required for therapeutic efficacy and is mediated by chemoattractants (cell adhesion molecules, cytokines, and growth factors). Homing processes are inefficient and depend on short-lived pathological inflammation that limits the window of opportunity for cell injections. Noninvasive pulsed focused ultrasound (pFUS), which emphasizes mechanical ultrasound–tissue interactions, can be precisely targeted in the body and is a promising approach to target and maximize stem cell delivery by stimulating chemoattractant expression in pFUS-treated tissue prior to cell infusions. We demonstrate that pFUS is nondestructive to murine skeletal muscle tissue (no necrosis, hemorrhage, or muscle stem cell activation) and initiates a largely M2-type macrophage response. We also demonstrate that local upregulation of chemoattractants in pFUS-treated skeletal muscle leads to enhance homing, permeability, and retention of human mesenchymal stem cells (MSC) and human endothelial precursor cells (EPC). Furthermore, the magnitude of MSC or EPC homing was increased when pFUS treatments and cell infusions were repeated daily. This study demonstrates that pFUS defines transient “molecular zip codes” of elevated chemoattractants in targeted muscle tissue, which effectively provides spatiotemporal control and tunability of the homing process for multiple stem cell types. pFUS is a clinically translatable modality that may ultimately improve homing efficiency and flexibility of cell therapies for cardiovascular diseases. Stem Cells 2013;31:2551–2560

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