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


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.
Segers
Vincent F M
VF
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, USA.
Tokunou
Tomotake
T
Higgins
Luke J
LJ
MacGillivray
Catherine
C
Gannon
Joseph
J
Lee
Richard T
RT
D000818:Animals; D001794:Blood Pressure; D002339:Carotid Arteries / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics* / Q000302:isolation & purification / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004351:Drug Resistance; D019650:Hematopoietic Stem Cell Mobilization; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009154:Mutation; D009203:Myocardial Infarction / Q000503:physiopathology*; D018919:Neovascularization, Physiologic; D010447:Peptide Hydrolases / Q000378:metabolism; D010957:Plasmids; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D013234:Stem Cells / Q000502:physiology*
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D010447:Peptide Hydrolases; D018819:Dipeptidyl Peptidase 4; D020778:Matrix Metalloproteinase 2