Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4.
Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4.
复制标题
DOI：
10.1371/journal.pone.0179257
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Ran S
中科院分区：
文献类型：
--
作者：
Volk-Draper LD;Hall KL;Wilber AC;Ran S
骨髓来源的淋巴管内皮细胞（M-LECP）是由炎症诱导的，在成人淋巴管生成中起重要作用。然而，驱动M-LECP分化的机制目前尚不清楚。我们先前表明，Toll样受体-4（TLR 4）的激活诱导永生化小鼠髓系细胞的髓样淋巴转化（MLT）。在这里，目标是评估不同的TLR 4配体诱导人类和小鼠原代骨髓细胞中的前淋巴重编程的潜力，并确定调节该过程的转录变化。人和小鼠骨髓细胞通过TLR 4配体（包括脂多糖（LPS）、重组高迁移率族蛋白1（HMGB 1）和紫杉醇）重编程为淋巴表型。TLR 4在来自不同品系和免疫状态的小鼠的细胞中诱导相似的MLT。通过来自免疫活性或免疫缺陷小鼠的人和小鼠骨髓细胞中的转录谱来检测常见诱导基因。共同的趋势包括：（1）血管特异性标志物血管内皮生长因子受体-3（VEGFR-3）、淋巴管内皮透明质酸受体-1（LYVE-1）和podoplanin（PDPN）的新表达在诱导前基本上不存在;（3）血管内皮生长因子-C（VEGF-C）和多种炎性细胞因子表达持续增加，血管内皮生长因子-3（VEGFR-3）表达短暂;（4）VEGFR-3上调和其它LEC基因对NF-κB的依赖性;和（5）新的细胞特异性（例如，PROX 1）和干/祖细胞（例如，E2 F1）转录因子，因其在成人和胚胎血管形成中的作用而闻名。TLR 4配体在体外产生的M-LECP在体内是有功能的，如在原位乳腺癌模型中检测到的显著增加的淋巴管密度和淋巴转移所证明的。我们建立了一种新的TLR 4依赖的协议，在体外生产的功能主管M-LECP从原代人类或小鼠骨髓细胞，并确定了许多潜在的监管机构，这一进程。这些信息可以进一步用于研究和治疗目的。
Myeloid-derived lymphatic endothelial cells (M-LECP) are induced by inflammation and play an important role in adult lymphangiogenesis. However, the mechanisms driving M-LECP differentiation are currently unclear. We previously showed that activation of Toll-like receptor-4 (TLR4) induces myeloid-lymphatic transition (MLT) of immortalized mouse myeloid cells. Here the goals were to assess the potential of different TLR4 ligands to induce pro-lymphatic reprogramming in human and mouse primary myeloid cells and to identify transcriptional changes regulating this process. Human and mouse myeloid cells were reprogrammed to the lymphatic phenotype by TLR4 ligands including lipopolysaccharide (LPS), recombinant high mobility group box 1 protein (HMGB1), and paclitaxel. TLR4 induced similar MLT in cells from mice of different strains and immune status. Commonly induced genes were detected by transcriptional profiling in human and mouse myeloid cells from either immunocompetent or immunodeficient mice. Shared trends included: (1) novel expression of lymphatic-specific markers vascular endothelial growth factor receptor-3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin (PDPN) largely absent prior to induction; (2) lack of notable changes in blood vessel-specific markers; (3) transient expression of VEGFR-3, but sustained increase of vascular endothelial growth factor-C (VEGF-C) and a variety of inflammatory cytokines; (4) dependency of VEGFR-3 upregulation and other LEC genes on NF-κB; and (5) novel expression of lymphatic-specific (e.g., PROX1) and stem/progenitor (e.g., E2F1) transcription factors known for their roles in adult and embryonic vascular formation. M-LECP generated by TLR4 ligands in vitro were functional in vivo as demonstrated by significantly increased lymphatic vessel density and lymphatic metastasis detected in orthotopic breast cancer models. We established a novel TLR4-dependent protocol for in vitro production of functionally competent M-LECP from primary human or mouse myeloid cells and identified many potential regulators of this process. This information can be further exploited for research and therapeutic purposes.