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- Open Access
Reestablishment of perfusion in critical limb ischemia model with pulsed focused ultrasound (pFUS) and mesenchymal stem cells in aged mice
© Tebebi et al; licensee BioMed Central Ltd. 2015
Published: 30 June 2015
Severe chronic peripheral arterial disease (PAD) manifests as critical limb ischemia (CLI) with a 5-year mortality rate >70%. Mesenchymal stem cells (MSC) show promise to minimize CLI progression and restore perfusion in experimental models, but approaches suffer from minimal homing to ischemic tissue and require clinically impractical direct injections of cells. We show that pulsed focused ultrasound (pFUS) noninvasively establishes a “molecular zip-code” of locally upregulated chemoattractants (i.e. cytokines, chemokines, cell adhesion molecules) that lead to enhanced homing permeability and retention of IV-infused MSC to pFUS-treated muscle. This study investigated if pFUS could enhance MSC homing in a CLI model in aged mice and whether they could ultimately improve limb perfusion.
CLI was induced by ligating the external iliac artery in C3H mice (9-12 months old). At 14 days post-CLI, mice were grouped as followed: saline controls (n=8); pFUS alone (n=7), MSC alone (n=8), or MSC+pFUS (n=17). Mice were treated, according to their group, daily for 3 days (i.e, 3×pFUS, 3×MSC, 3×MSC+pFUS). pFUS was applied to ischemic hamstrings at 40W (5% duty cycle, 5Hz PRF, 100 pulses). For mice receiving MSC, 106 MSC were IV injected via the lateral tail vein. Mice receiving pFUS+MSC had MSC injected ~1hr pre-pFUS. To assess MSC homing, mice were euthanized at 15 days post-CLI (24 hr after last treatment). Fe-labeled MSC were counted by microscopy after Prussian Blue staining. Laser Doppler perfusion imaging (LDPI) was performed weekly for 7-8 weeks post-treatment.
Results and conclusions
Funding is sponsered by the Intramural Research Program at the NIH.
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