Healing of injured tissues involves the activities of at least two functionally distinct subsets of monocytes. Recruitment of Ly-6Chi (“pro-inflammatory”) monocytes (IMs) from the blood is a hallmark response to injury or infection, whereas Ly-6Clo(“anti-inflammatory”) monocytes (AMs) patrol the resting endothelium and facilitate inflammation resolution. Key roles for the recruitment kinetics of functionally distinct monocyte subsets have been described for a diversity of clinical problems, including segmental bone repair, spinal cord injury recovery, liver fibrosis resolution, and both skeletal and myocardial muscle regeneration. Though understanding mechanisms that direct respective contributions of these two populations during normal wound healing is rapidly advancing, development of immunologically smart delivery strategies that can exploit the division of labor among functionally distinct monocyte-macrophage subsets to enhance regeneration remains a grand challenge. In this study, we will demonstrate that anti-inflammatory AMs may be functionally distinguished from  IMs by higher surface expression of sphingosine 1-phosphate receptor subtype  3 (S1P3) as well as increased CXCR4 mediated chemotaxis. Sustained release of S1P3 receptor-targeted agonist FTY720 in vivo recruits AMs to a vascular niche surrounding peri-implant arterioles and increases production of so-called “angiocrine” factors known to stimulate organ and tissue repair. To exploit these insights for tissue engineering and drug delivery applications, we used CXCR4 priming hydrogels containing heparin that precisely control release kinetics of FTY720 and release of heparin binding growth factors, including the cognate CXCR4 ligand SDF-1α. Preliminary in vivo studies employing non-degradable heparin-based hydrogels suggests that co-delivery of FTY720 with SDF-1α significantly increases recruitment of CXCR4+ cells to the implant area, increases the % of recruited monocytes that exhibited the AM phenotype, and increases the number of (“anti-inflammatory”) M2 macrophages associated with tissue repair.<br/>

Materials for angiocrine factor delivery and harnessing of pro-regenerative inflammation

249th National Meeting (2015)

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