IL-10 promotes endothelial progenitor cell infiltration and wound healing via STAT3.
IL-10 promotes endothelial progenitor cell infiltration and wound healing via STAT3.
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白细胞介素 - 10通过信号转导及转录激活因子3促进内皮祖细胞浸润和伤口愈合。
DOI：
10.1096/fj.201901024rr
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发表时间：
2022-07
期刊：
影响因子：
--
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中科院分区：
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内皮祖细胞（EPCs）有助于新生血管生成，组织再生和重塑。白细胞介素10（IL-10）是一种主要通过STAT 3发出信号的抗炎细胞因子，已被证明可以驱动EPC募集到受损组织。我们之前的工作表明，皮肤伤口中IL-10的过表达通过成纤维细胞特异性透明质酸合成的STAT 3依赖性调节促进再生组织修复。然而，IL-10对EPC募集的作用和具体作用方式，特别是在正常和糖尿病伤口的真皮伤口愈合和新生血管形成中的作用，仍有待确定。因此，研究了诱导型皮肤特异性STAT 3敲低小鼠，以确定IL-10对EPC、真皮伤口新生血管形成和愈合的影响，以及是否依赖于STAT 3。我们发现，IL-10过表达显著提高了肉芽创面床中的EPC计数，这与第7天对照和糖尿病（db/db）伤口的稳健毛细血管腔密度和增强的上皮再形成相关。我们注意到伤口中VEGF和高C-X-C基序趋化因子12（CXCL 12）水平增加，并且第3天出现有利的CXCL 12梯度，这可能支持EPC动员和从骨髓向伤口的浸润，这种作用在STAT 3敲除伤口中被消除。这些发现在体外得到了支持。IL-10促进原代鼠皮肤成纤维细胞中VEGF和CXCL 12的合成，通过抗体结合阻断培养基中的CXCL 12后，VEGF表达减弱。IL-10条件成纤维细胞培养基也显著促进内皮发芽和网络形成。总之，这些研究表明，皮肤伤口中IL-10的过表达招募了EPC，并导致血管结构增加和更快的再上皮化。
Endothelial progenitor cells (EPCs) contribute to de novo angiogenesis, tissue regeneration, and remodeling. Interleukin 10 (IL‐10), an anti‐inflammatory cytokine that primarily signals via STAT3, has been shown to drive EPC recruitment to injured tissues. Our previous work demonstrated that overexpression of IL‐10 in dermal wounds promotes regenerative tissue repair via STAT3‐dependent regulation of fibroblast‐specific hyaluronan synthesis. However, IL‐10's role and specific mode of action on EPC recruitment, particularly in dermal wound healing and neovascularization in both normal and diabetic wounds, remain to be defined. Therefore, inducible skin‐specific STAT3 knockdown mice were studied to determine IL‐10's impact on EPCs, dermal wound neovascularization and healing, and whether it is STAT3‐dependent. We show that IL‐10 overexpression significantly elevated EPC counts in the granulating wound bed, which was associated with robust capillary lumen density and enhanced re‐epithelialization of both control and diabetic (db/db) wounds at day 7. We noted increased VEGF and high C‐X‐C motif chemokine 12 (CXCL12) levels in wounds and a favorable CXCL12 gradient at day 3 that may support EPC mobilization and infiltration from bone marrow to wounds, an effect that was abrogated in STAT3 knockdown wounds. These findings were supported in vitro. IL‐10 promoted VEGF and CXCL12 synthesis in primary murine dermal fibroblasts, with blunted VEGF expression upon blocking CXCL12 in the media by antibody binding. IL‐10‐conditioned fibroblast media also significantly promoted endothelial sprouting and network formation. In conclusion, these studies demonstrate that overexpression of IL‐10 in dermal wounds recruits EPCs and leads to increased vascular structures and faster re‐epithelialization.
影响因子：
9.7
作者：
Cho, Hongkwan;Balaji, Swathi;Sheikh, Abdul Q.;Hurley, Jennifer R.;Tian, Ye F.;Collier, Joel H.;Crombleholme, Timothy M.;Narmoneva, Daria A.
通讯作者：
Narmoneva, Daria A.