Vascular gene transfer of SDF-1 promotes endothelial progenitor cell engraftment and enhances angiogenesis in ischemic muscle

Michael A. Kuliszewski; Jeremy Kobulnik; Jonathan R. Lindner; Duncan J. Stewart; Howard Leong-Poi

doi:10.1038/mt.2011.18

Vascular gene transfer of SDF-1 promotes endothelial progenitor cell engraftment and enhances angiogenesis in ischemic muscle

Michael A. Kuliszewski
, Jeremy Kobulnik
, Jonathan R. Lindner
, Duncan J. Stewart
, Howard Leong-Poi

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

Abstract

Gene therapy approaches to enhance endothelial progenitor cell (EPC) homing may augment cell engraftment to ischemic tissue and lead to a greater therapeutic response. Therefore, we assessed the effects of ultrasound-mediated (UM) transfection of the chemokine stromal cell-derived factor-1 (SDF-1) on homing and engraftment of intravenously administered EPCs and the subsequent angiogenic response in chronically ischemic skeletal muscle. Bone marrow-derived EPCs were isolated from donor Fisher 344 rats, cultured and labeled in preparation for injection into recipient animals via a jugular vein. Using a model of chronic hindlimb ischemia in rats, we demonstrated that UM destruction of intravenous carrier microbubbles loaded with SDF-1 plasmid DNA resulted in targeted transfection of the vascular endothelium within ischemic muscle and greater local engraftment of EPCs. The combination of SDF-1gene therapy and EPCs lead to the greatest increase in tissue perfusion and microvascular density within ischemic muscle, compared to no treatment or either monotherapy alone. Our results demonstrate that UM transfection of SDF-1 improves EPC targeting to chronically ischemic tissue, enhancing vascular engraftment and leading to a more robust neovascularization response.

Original language	English (US)
Pages (from-to)	895-902
Number of pages	8
Journal	Molecular Therapy
Volume	19
Issue number	5
DOIs	https://doi.org/10.1038/mt.2011.18
State	Published - May 2011

Funding

This work was supported by an Operating Grant (FRN 62763) from the Canadian Institutes of Health Research, Ottawa, Ontario, Canada, and an Equipment Grant from the Canadian Foundation for Innovation, Ottawa, Ontario, Canada. J.R.L. is supported by grants R01-HL-074443, R01-HL-078610, and R01-DK-063508 from the National Institutes of Health, Bethesda, MD. H.L.-P. is supported by a Phase II Clinician Scientist Award, Heart and Stroke Foundation of Ontario, Ottawa, Ontario, Canada and an Early Researcher Award from the Ministry of Research and Innovation, Ontario, Canada. The authors declared no conflict of interest.

Funders	Funder number
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health
Canadian Institutes of Health Research
Canada Foundation for Innovation/Ontario Innovation Trust	R01-DK-063508, R01-HL-078610, R01-HL-074443
Ontario Ministry of Research, Innovation and Science

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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10.1038/mt.2011.18

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title = "Vascular gene transfer of SDF-1 promotes endothelial progenitor cell engraftment and enhances angiogenesis in ischemic muscle",

abstract = "Gene therapy approaches to enhance endothelial progenitor cell (EPC) homing may augment cell engraftment to ischemic tissue and lead to a greater therapeutic response. Therefore, we assessed the effects of ultrasound-mediated (UM) transfection of the chemokine stromal cell-derived factor-1 (SDF-1) on homing and engraftment of intravenously administered EPCs and the subsequent angiogenic response in chronically ischemic skeletal muscle. Bone marrow-derived EPCs were isolated from donor Fisher 344 rats, cultured and labeled in preparation for injection into recipient animals via a jugular vein. Using a model of chronic hindlimb ischemia in rats, we demonstrated that UM destruction of intravenous carrier microbubbles loaded with SDF-1 plasmid DNA resulted in targeted transfection of the vascular endothelium within ischemic muscle and greater local engraftment of EPCs. The combination of SDF-1gene therapy and EPCs lead to the greatest increase in tissue perfusion and microvascular density within ischemic muscle, compared to no treatment or either monotherapy alone. Our results demonstrate that UM transfection of SDF-1 improves EPC targeting to chronically ischemic tissue, enhancing vascular engraftment and leading to a more robust neovascularization response.",

author = "Kuliszewski, \{Michael A.\} and Jeremy Kobulnik and Lindner, \{Jonathan R.\} and Stewart, \{Duncan J.\} and Howard Leong-Poi",

note = "Funding Information: This work was supported by an Operating Grant (FRN 62763) from the Canadian Institutes of Health Research, Ottawa, Ontario, Canada, and an Equipment Grant from the Canadian Foundation for Innovation, Ottawa, Ontario, Canada. J.R.L. is supported by grants R01-HL-074443, R01-HL-078610, and R01-DK-063508 from the National Institutes of Health, Bethesda, MD. H.L.-P. is supported by a Phase II Clinician Scientist Award, Heart and Stroke Foundation of Ontario, Ottawa, Ontario, Canada and an Early Researcher Award from the Ministry of Research and Innovation, Ontario, Canada. The authors declared no conflict of interest.",

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Vascular gene transfer of SDF-1 promotes endothelial progenitor cell engraftment and enhances angiogenesis in ischemic muscle

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