Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound.
Mesenchymal stem cells (MSC) are promising therapeutics for critical limb ischemia (CLI). Mechanotransduction from pulsed focused ultrasound (pFUS) upregulates local chemoattractants to enhance homing of intravenously (IV)-infused MSC and improve outcomes. This study investigated whether pFUS exposures to skeletal muscle would improve local homing of iv-infused MSCs and their therapeutic efficacy compared to iv-infused MSCs alone. CLI was induced by external iliac arterial cauterization in 10-12-month-old mice. pFUS/MSC treatments were delayed 14 days, when surgical inflammation subsided. Mice were treated with iv-saline, pFUS alone, IV-MSC, or pFUS and IV-MSC. Proteomic analyses revealed pFUS upregulated local chemoattractants and increased MSC tropism to CLI muscle. By 7 weeks post-treatment, pFUS + MSC significantly increased perfusion and CD31 expression, while reducing fibrosis compared to saline. pFUS or MSC alone reduced fibrosis, but did not increase perfusion or CD31. Furthermore, MSCs homing to pFUS-treated CLI muscle expressed more vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) than MSCs homing to non-pFUS-treated muscle. pFUS + MSC improved perfusion and vascular density in this clinically-relevant CLI model. The molecular effects of pFUS increased both MSC homing and MSC production of VEGF and IL-10, suggesting microenvironmental changes from pFUS also increased potency of MSCs in situ to further enhance their efficacy.
Frank Lab, Radiology and Imaging Sciences Dept., Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.|Department of Biomedical Engineering, Catholic University of America, Washington, DC, USA.
Pamela A
PA
Tebebi
Frank Lab, Radiology and Imaging Sciences Dept., Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Saejeong J
SJ
Kim
Frank Lab, Radiology and Imaging Sciences Dept., Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Rashida A
RA
Williams
Frank Lab, Radiology and Imaging Sciences Dept., Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Blerta
B
Milo
Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Victor
V
Frenkel
Frank Lab, Radiology and Imaging Sciences Dept., Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Scott R
SR
Burks
Frank Lab, Radiology and Imaging Sciences Dept., Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.|National Institutes of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA.
Joseph A
JA
Frank
D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D005121:Extremities / Q000098:blood supply* / Q000528:radiation effects; D005260:Female; D005355:Fibrosis; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D020543:Proteome; D040901:Proteomics / Q000379:methods; D015424:Reperfusion / Q000379:methods; D000069453:Ultrasonic Waves; D018615:Ultrasonography, Doppler, Color; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D020543:Proteome; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10