Abstract
Stromal cell-derived factor 1α (SDF1α) is a potent chemokine for the recruitment of stem cells. A challenge is to maintain its activity and control its release. In this study, we engineered a recombinant cysteine-SDF1α (cysSDF1α) protein, and performed multivalent conjugation of cysSDF1 through the maleimide functional group to two forms of branched nanoparticles: multi-arm poly (ethylene glycol) (MA-PEG) and hyaluronic acid (HA). We characterized the chemotactic activity of the conjugates, and determined how the molecular weight (MW) of MA-PEG and HA affected the chemotactic activity. CysSDF1α had similar efficiency to wild-type SDF1α in cell recruitment. Multivalent conjugation of cysSDF1α to low MW MA-PEG (~18 nm) did not significantly affect the chemotactic activity, while the conjugation of cysSDF1α to high MW MA-PEG (~72 nm) lowered the efficiency, possibly due to the larger spacing between conjugated SDF1α molecules. HA has a linear backbone and a high density of multivalent binding sites; however, the chemotactic activity of HA-linked cys-SDF1α was much lower, which further decreased with the increase of HA MW from 200 kDa (~0.78 μm) to 700 kDa (~2.7 μm). Digestion of HA into smaller fragments using hyaluronidase partially recovered the chemotactic activity of cysSDF1α, suggesting that high MW HA might exert steric hindrance for SDF1α binding to its receptors on cell surface and that HA could be used as a depot for SDF1α storage and release. These results demonstrate that multivalent conjugates of SDF1α to nanoparticles may be used to engineer SDF1α delivery for cell recruitment and tissue regeneration.
Highlights
Stromal cell-derived factor 1α (SDF1α) is a chemokine released by bone marrow stromal cells for homing hematopoietic stem cells (HSCs) via a receptor-ligand CXCR4-CXCL12 interaction [1] [2] [3]
Digestion of hyaluronic acid (HA) into smaller fragments using hyaluronidase partially recovered the chemotactic activity of cysSDF1α, suggesting that high molecular weight (MW) HA might exert steric hindrance for SDF1α binding to its receptors on cell surface and that HA could be used as a depot for SDF1α storage and release
These results demonstrate that multivalent conjugates of SDF1α to nanoparticles may be used to engineer SDF1α delivery for cell recruitment and tissue regeneration
Summary
Stromal cell-derived factor 1α (SDF1α) is a chemokine released by bone marrow stromal cells for homing hematopoietic stem cells (HSCs) via a receptor-ligand CXCR4-CXCL12 interaction [1] [2] [3]. SDF1α can be released upon tissue injury and recruit bone marrow cells, stem cells and progenitor cells for tissue regeneration [4]-[11]. It has been shown that clustering of vascular endothelial growth factors [25], fibroblast growth factor-2 [26], or epidermal growth factors synergistically increases the activity by inducing receptor dimerization [27]. It is not clear whether multivalent conjugation of SDF1α onto nanoparticles affects its activity and potency
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