Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13785-90. doi: 10.1073/pnas.1221309110. Epub 2013 Aug 5.
Endothelial cells play significant roles in conditioning tissues after injury by the production and secretion of angiocrine factors. At least two distinct subsets of monocytes, CD45(+)CD11b(+)Gr1(+)Ly6C(+) inflammatory and CD45(+)CD11b(+)Gr1(-)Ly6C(-) anti-inflammatory monocytes, respond differentially to these angiocrine factors and promote pathogen/debris clearance and arteriogenesis/tissue regeneration, respectively. We demonstrate here that local sphingosine 1-phosphate receptor 3 (S1P3) agonism recruits anti-inflammatory monocytes to remodeling vessels. Poly(lactic-co-glycolic acid) thin films were used to deliver FTY720, an S1P1/3 agonist, to inflamed and ischemic tissues, which resulted in a reduction in proinflammatory cytokine secretion and an increase in regenerative cytokine secretion. The altered balance of cytokine secretion results in preferential recruitment of anti-inflammatory monocytes from circulation. The chemotaxis of these cells, which express more S1P3 than inflammatory monocytes, toward SDF-1α was also enhanced with FTY720 treatment, but not in S1P3 knockout cells. FTY720 delivery enhanced arteriolar diameter expansion and increased length density of the local vasculature. This work establishes a role for S1P receptor signaling in the local conditioning of tissues by angiocrine factors that preferentially recruit regenerative monocytes that can enhance healing outcomes, tissue regeneration, and biomaterial implant functionality.
内皮细胞通过分泌血管生成因子在组织损伤后发挥重要作用。至少有两种不同的单核细胞亚群，CD45(+)CD11b(+)Gr1(+)Ly6C(+)炎症性和 CD45(+)CD11b(+)Gr1(-)Ly6C(-)抗炎性单核细胞，对这些血管生成因子的反应不同，并分别促进病原体/碎片清除和动脉生成/组织再生。我们在这里证明，局部鞘氨醇 1-磷酸受体 3 (S1P3) 激动剂募集抗炎性单核细胞以重塑血管。聚（乳酸-共-乙醇酸）薄膜用于将 S1P1/3 激动剂 FTY720 递送至炎症和缺血组织，导致促炎细胞因子分泌减少和再生细胞因子分泌增加。细胞因子分泌的平衡改变导致抗炎性单核细胞从循环中优先募集。这些细胞的趋化性，即表达比炎症性单核细胞更多的 S1P3，也因 FTY720 处理而增强，但在 S1P3 敲除细胞中则不然。FTY720 的递送增强了小动脉直径的扩张，并增加了局部血管的长度密度。这项工作确立了 S1P 受体信号在组织通过血管生成因子进行局部调节中的作用，这些因子优先募集具有增强愈合效果、组织再生和生物材料植入功能的再生性单核细胞。
