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.
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.
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; Imaging Sciences Training Program, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA.
Scott R
SR
Burks
Ali
A
Ziadloo
Saejeong J
SJ
Kim
Ben A
BA
Nguyen
Joseph A
JA
Frank
D000818:Animals; D018929:Cell Culture Techniques; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism*; D062211:Spatio-Temporal Analysis; D013234:Stem Cells / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism*; D014465:Ultrasonics / Q000379:methods*; D014463:Ultrasonography
D016207:Cytokines
Endothelial precursor cells; High intensity focused ultrasound; Mesenchymal stem cells; Pulsed focused ultrasound; Stem cells; Targeted delivery