Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction

Vincent F.M. Segers, Tomotake Tokunou, Luke J. Higgins, Catherine MacGillivray, Joseph Gannon, Richard T. Lee

Research output: Contribution to journalArticle

271 Citations (Scopus)

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 mm). 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.

Original languageEnglish
Pages (from-to)1683-1692
Number of pages10
JournalCirculation
Volume116
Issue number15
DOIs
Publication statusPublished - Oct 1 2007
Externally publishedYes

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Chemokine CXCL12
Peptide Hydrolases
Stem Cells
Chemokines
Myocardial Infarction
Nanofibers
Exopeptidases
Regeneration
Matrix Metalloproteinase 2
Chemotactic Factors
Neurotoxins
Chemotaxis
Dementia
Proteins
Peptides

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. / Segers, Vincent F.M.; Tokunou, Tomotake; Higgins, Luke J.; MacGillivray, Catherine; Gannon, Joseph; Lee, Richard T.

In: Circulation, Vol. 116, No. 15, 01.10.2007, p. 1683-1692.

Research output: Contribution to journalArticle

Segers, Vincent F.M. ; Tokunou, Tomotake ; Higgins, Luke J. ; MacGillivray, Catherine ; Gannon, Joseph ; Lee, Richard T. / Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. In: Circulation. 2007 ; Vol. 116, No. 15. pp. 1683-1692.
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AU - MacGillivray, Catherine

AU - Gannon, Joseph

AU - Lee, Richard T.

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AB - 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 mm). 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.

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