Local Delivery of Protease-Resistant Stromal Cell Derived Factor-1 for Stem Cell Recruitment After Myocardial Infarction

TLDR

Local delivery of chemokines for tissue regeneration is limited by rapid diffusion and protease cleavage, and although SDF‑1 attracts stem cells, it is degraded by exopeptidases and MMP‑2, producing neurotoxic fragments. The authors engineered a protease‑resistant SDF‑1 variant, S‑SDF‑1(S4V), fused to self‑assembling peptide nanofibers that tether the chemokine for localized delivery. Intramyocardial delivery of S‑SDF‑1(S4V) nanofibers recruited CXCR4⁺/c‑Kit⁺ stem cells, increased capillary density, and improved ejection fraction from 34 % to 51 % in 176 rats, demonstrating that local chemokine delivery promotes stem‑cell recruitment and cardiac repair.

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 2 ). 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.