A controlled release system for simultaneous delivery of three human perivascular stem cell-derived factors for tissue repair and regeneration

Transplanted stem/progenitor cells improve tissue healing and regeneration anatomically and functionally, mostly due to their secreted trophic factors. However, harsh conditions at the site of injury, including hypoxia, oxidative and inflammatory stress, increased fibrosis and insufficient angiogenesis, and in some cases immunological response or incompatibility, are detrimental to stem cell survival. To overcome the complexity and deficiencies of stem cell therapy, the coacervate delivery platform is deemed promising because it offers controlled and sustained release using heparin to recapitulate the binding and stabilization of extracellular proteins by heparan sulphates in native tissues. Here we show that recombinant alternatives of three key factors [vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6)], commonly produced by perivascular stem cells under various stress conditions, can be successfully incorporated into a heparin-based coacervate. We characterized the release profile of the triply incorporated factors from the complex coacervate. The coacervate-released factors were able to exert their desired biological activities in vitro: VEGF stimulated human umbilical vein endothelial cell proliferation, MCP-1 elevated macrophage migration and IL-6 increased IgM production by IL-6-dependent cell line. Thus, a controlled release system can be used for simultaneous delivery of three stem cell-derived factors and could be useful for tissue repair and regenerative medicine.