A stromal cell-derived factor-1 releasing matrix enhances the progenitor cell response and blood vessel growth in ischaemic skeletal muscle

Abstract

Although many regenerative cell therapies are being developed to replace or regenerate ischaemic muscle, the lack of vasculature and poor persistence of the therapeutic cells represent major limiting factors to successful tissue restoration. In response to ischaemia, stromal cellderived factor-1 (SDF-1) is up-regulated by the affected tissue to stimulate stem cell-mediated regenerative responses. Therefore, we encapsulated SDF-1 into alginate microspheres and further incorporated these into an injectable collagen-based matrix in order to improve local delivery. Microsphere-matrix impregnation reduced the time for matrix thermogelation, and also increased the viscosity reached. This double-incorporation prolonged the release of SDF-1, which maintained adhesive and migratory bioactivity, attributed to chemotaxis in response to SDF-1. In vivo, treatment of ischaemic hindlimb muscle with microsphere-matrix led to increased mobilisation of bone marrow-derived progenitor cells, and also improved recruitment of angiogenic cells expressing the SDF-1 receptor (CXCR4) from bone marrow and local tissues. Both matrix and SDF-1-releasing matrix were successful at restoring perfusion, but SDF-1 treatment appeared to play an earlier role, as evidenced by arterioles that are phenotypically older and by increased angiogenic cytokine production, stimulating the generation of a qualitative microenvironment for a rapid and therefore more effi cient regeneration. These results support the release of implanted SDF-1 as a promising method for enhancing progenitor cell responses and restoring perfusion to ischaemic tissues via neovascularisation.

Tertiary Biomaterial Encapsulation Controls the Release of FGF-2 without Impacting Bioactivity

“…A similar model has also shown this effect of reduced burst release effect, but using stromal cellderived factor-1-containing alginate microparticles and an injectable collagen-chondroitin sulfate hydrogel [20]. Notably, in the current study, tertiary encapsulation into a Fig.…”

“…As previously described [20], blood samples (50-100μl) were procured from the saphenous veins prior-to surgery and after 1 and 2 weeks. Peripheral blood mononuclear cells were isolated using density-gradient centrifugation.…”

Injectable skeletal muscle matrix hydrogel promotes neovascularization and muscle cell infiltration in a hindlimb ischemia model

“…PLGA microspheres in alginate hydrogels have been utilized to deliver vascular endothelial growth factor (VEGF) (Lee et al, 2010), and alginate hydrogels have been explored for delivery of hepatocyte growth factor (HGF) (Ruvinov et al, 2010), VEGF (Silva and Mooney, 2007), and pDNA encoding for VEGF (Kong et al, 2008). Alginate microspheres within an injectable collagen matrix have also been used to deliver stromal cell-derived factor-1 (SDF-1) (Kuraitis et al, 2011), while VEGF-loaded alginate microparticles in a collagen-fibronectin scaffold were used to deliver endothelial cells (Jay et al, 2008). Gelatin hydrogels have been employed to deliver basic fibroblast growth factor (bFGF) (Doi et al, 2007;Layman et al, 2007), and fibrin scaffolds were utilized to deliver bFGF and granulocyte-colony stimulating factor (G-CSF) along with bone marrow cells.…”

“…Biomaterials have also been used for delivery of growth factors or their mimics in animal models of PAD and CLI (Kawamoto et al, 2009;Layman et al, 2011;Ruvinov et al, 2010;Webber et al, 2011). However, these scaffolds are composed of fibrin (Layman et al, 2011), collagen-based matrix (Kuraitis et al, 2011), gelatin (Layman et al, 2007), self-assembling peptide amphiphiles (Webber et al, 2011) or alginate (Ruvinov et al, 2010), which may not provide the proper biomimetic environment for the ischemic skeletal muscle in these conditions. Moreover, no potential therapies employing only a biomaterial have been explored to date.…”

CXCL12/Stromal-Cell-Derived Factor-1 Effectively Replaces Endothelial Progenitor Cells to Induce Vascularized Ectopic Bone

“…Another strategy to improve vascularization of implants is the inclusion of growth factors that promote angiogenesis, such as vascular endothelial growth factor [16][17][18][19] and C-X-C motif ligand 12/stromal cell-derived factor-1a (CXCL12/ SDF-1a) [20][21][22]. SDF-1a is known to be active as a potent cell-homing factor [23][24][25] through binding to its CXCR4 receptor [26] and has been proven to induce tubule formation by ECs in vitro [20,21] as well as angiogenesis in tissueengineered grafts in vivo [20,23,27].…”