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Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction.
Circulation. 2007 Oct 09; 116(15):1683-92.Circ

Abstract

BACKGROUND

Local delivery of chemotactic factors represents a novel approach to tissue regeneration. However, successful chemokine protein delivery is challenged by barriers including the rapid diffusion of chemokines and cleavage of chemokines by proteases that are activated in injured tissues. Stromal cell-derived factor-1 (SDF-1) is a well-characterized chemokine for attracting stem cells and thus a strong candidate for promoting regeneration. However, SDF-1 is cleaved by exopeptidases and matrix metalloproteinase-2, generating a neurotoxin implicated in some forms of dementia.

METHODS AND RESULTS

We designed a new chemokine called S-SDF-1(S4V) that is resistant to matrix metalloproteinase-2 and exopeptidase cleavage but retains chemotactic bioactivity, reducing the neurotoxic potential of native SDF-1. To deliver S-SDF-1(S4V), we expressed and purified fusion proteins to tether the chemokine to self-assembling peptides, which form nanofibers and allow local delivery. Intramyocardial delivery of S-SDF-1(S4V) after myocardial infarction recruited CXCR4+/c-Kit+ stem cells (46+/-7 to 119+/-18 cells per section) and increased capillary density (from 169+/-42 to 283+/-27 per 1 mm2). Furthermore, in a randomized, blinded study of 176 rats with myocardial infarction, nanofiber delivery of the protease-resistant S-SDF-1(S4V) improved cardiac function (ejection fraction increased from 34.0+/-2.5% to 50.7+/-3.1%), whereas native SDF-1 had no beneficial effects.

CONCLUSIONS

The combined advances of a new, protease-resistant SDF-1 and nanofiber-mediated delivery promoted recruitment of stem cells and improved cardiac function after myocardial infarction. These data demonstrate that driving chemotaxis of stem cells by local chemokine delivery is a promising new strategy for tissue regeneration.

Authors+Show Affiliations

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17875967

Citation

Segers, Vincent F M., et al. "Local Delivery of Protease-resistant Stromal Cell Derived Factor-1 for Stem Cell Recruitment After Myocardial Infarction." Circulation, vol. 116, no. 15, 2007, pp. 1683-92.
Segers VF, Tokunou T, Higgins LJ, et al. Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. Circulation. 2007;116(15):1683-92.
Segers, V. F., Tokunou, T., Higgins, L. J., MacGillivray, C., Gannon, J., & Lee, R. T. (2007). Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. Circulation, 116(15), 1683-92.
Segers VF, et al. Local Delivery of Protease-resistant Stromal Cell Derived Factor-1 for Stem Cell Recruitment After Myocardial Infarction. Circulation. 2007 Oct 9;116(15):1683-92. PubMed PMID: 17875967.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. AU - Segers,Vincent F M, AU - Tokunou,Tomotake, AU - Higgins,Luke J, AU - MacGillivray,Catherine, AU - Gannon,Joseph, AU - Lee,Richard T, Y1 - 2007/09/17/ PY - 2007/9/19/pubmed PY - 2007/11/14/medline PY - 2007/9/19/entrez SP - 1683 EP - 92 JF - Circulation JO - Circulation VL - 116 IS - 15 N2 - BACKGROUND: Local delivery of chemotactic factors represents a novel approach to tissue regeneration. However, successful chemokine protein delivery is challenged by barriers including the rapid diffusion of chemokines and cleavage of chemokines by proteases that are activated in injured tissues. Stromal cell-derived factor-1 (SDF-1) is a well-characterized chemokine for attracting stem cells and thus a strong candidate for promoting regeneration. However, SDF-1 is cleaved by exopeptidases and matrix metalloproteinase-2, generating a neurotoxin implicated in some forms of dementia. METHODS AND RESULTS: We designed a new chemokine called S-SDF-1(S4V) that is resistant to matrix metalloproteinase-2 and exopeptidase cleavage but retains chemotactic bioactivity, reducing the neurotoxic potential of native SDF-1. To deliver S-SDF-1(S4V), we expressed and purified fusion proteins to tether the chemokine to self-assembling peptides, which form nanofibers and allow local delivery. Intramyocardial delivery of S-SDF-1(S4V) after myocardial infarction recruited CXCR4+/c-Kit+ stem cells (46+/-7 to 119+/-18 cells per section) and increased capillary density (from 169+/-42 to 283+/-27 per 1 mm2). Furthermore, in a randomized, blinded study of 176 rats with myocardial infarction, nanofiber delivery of the protease-resistant S-SDF-1(S4V) improved cardiac function (ejection fraction increased from 34.0+/-2.5% to 50.7+/-3.1%), whereas native SDF-1 had no beneficial effects. CONCLUSIONS: The combined advances of a new, protease-resistant SDF-1 and nanofiber-mediated delivery promoted recruitment of stem cells and improved cardiac function after myocardial infarction. These data demonstrate that driving chemotaxis of stem cells by local chemokine delivery is a promising new strategy for tissue regeneration. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/17875967/Local_delivery_of_protease_resistant_stromal_cell_derived_factor_1_for_stem_cell_recruitment_after_myocardial_infarction_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.107.718718?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -