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

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 ϩ /c-Kit ϩ stem cells (46Ϯ7 to 119Ϯ18 cells per section) and increased capillary density (from 169Ϯ42 to 283Ϯ27 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 34.0Ϯ2.5% to 50.7Ϯ3.1%), 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. (Circulation.

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…39,40 Currently, there are research efforts to utilize this mechanism by local intramyocardial delivery of a protease-resistant CXCL12 to attract progenitor cells to sites of hypoxic damage after myocardial infarction. 41 Moreover, in hypoxic tumors or in tumors that display mutations in the von Hippel-Lindau tumor suppressor protein pVHL (a negative regulator of HIF-1), HIF-1 upregulates CXCR4 expression, 42,43 providing a survival benefit for tumor cells with high CXCR4 expression.…”

Injectable Acellular Hydrogels for Cardiac Repair

“…For example, stromal derived factor-1 alpha (SDF-1α) has been locally delivered in the setting of MI using the self-assembling peptide hydrogels described in the previous section [98]. Release of SDF-1α was controlled by tethering the protein to the oligopeptide scaffold through a peptide sequence that is cleaved by endogenous proteases.…”

Heart regeneration after myocardial infarction using synthetic biomaterials

“…In this case, SDF-1 variant resistant to protease degradation was encapsulated into hydrogels and administered in a rat MI model. Treatment resulted in significant enhancements on SC recruitment, improved cardiac function and capillary density 28 days after administration [79]. Interestingly, when animals were treated with the SDF-1 resistant variant, a better heart recovery was observed compared to the normal SDF-1 treated group, although no significant differences were reported.…”