Liao Ko-Hsun, Chang Shing-Jyh, Chang Hsin-Chuan, Chien Chen-Li, Huang Tse-Shun, Feng Te-Chia, Lin Wen-Wei, Shih Chuan-Chi, Yang Muh-Hwa, Yang Shung-Haur, Lin Chi-Hung, Hwang Wei-Lun, Lee Oscar K
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan.
PLoS One. 2017 Jun 22;12(6):e0179758. doi: 10.1371/journal.pone.0179758. eCollection 2017.
Tissue angiogenesis is intimately regulated during embryogenesis and postnatal development. Defected angiogenesis contributes to aberrant development and is the main complication associated with ischemia-related diseases. We previously identified the increased expression of RUNX1T1 in umbilical cord blood-derived endothelial colony-forming cells (ECFCs) by gene expression microarray. However, the biological relevance of RUNX1T1 in endothelial lineage is not defined clearly. Here, we demonstrate RUNX1T1 regulates the survival, motility and tube forming capability of ECFCs and EA.hy926 endothelial cells by loss-and gain-of function assays, respectively. Second, embryonic vasculatures and quantity of bone marrow-derived angiogenic progenitors are found to be reduced in the established Runx1t1 heterozygous knockout mice. Finally, a central RUNX1T1-regulated signature is uncovered and VEGFA, BMP4 as well as TGF-β2 are demonstrated to mediate RUNX1T1-orchested angiogenic activities. Taken together, our results reveal that RUNX1T1 serves as a common angiogenic driver for vaculogenesis and functionality of endothelial lineage cells. Therefore, the discovery and application of pharmaceutical activators for RUNX1T1 will improve therapeutic efficacy toward ischemia by promoting neovascularization.
组织血管生成在胚胎发育和出生后发育过程中受到密切调控。血管生成缺陷会导致发育异常，并且是与缺血相关疾病相关的主要并发症。我们之前通过基因表达微阵列鉴定出脐带血来源的内皮集落形成细胞（ECFCs）中RUNX1T1的表达增加。然而，RUNX1T1在内皮谱系中的生物学相关性尚未明确界定。在此，我们分别通过功能缺失和功能获得实验证明，RUNX1T1调节ECFCs和EA.hy926内皮细胞的存活、迁移和管形成能力。其次，在已建立的Runx1t1杂合敲除小鼠中，发现胚胎血管系统和骨髓来源的血管生成祖细胞数量减少。最后，揭示了一个由RUNX1T1调控的核心特征，并证明VEGFA、BMP4以及TGF-β2介导RUNX1T1协调的血管生成活性。综上所述，我们的结果表明RUNX1T1作为血管生成和内皮谱系细胞功能的共同血管生成驱动因子。因此，RUNX1T1药物激活剂的发现和应用将通过促进新血管形成提高对缺血的治疗效果。
