Notch ligand Delta-like 1 promotes in vivo vasculogenesis in human cord blood-derived endothelial colony forming cells.
Notch ligand Delta-like 1 promotes in vivo vasculogenesis in human cord blood-derived endothelial colony forming cells.
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DOI：
10.1016/j.jcyt.2014.12.003
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发表时间：
2015-05
期刊：
影响因子：
4.5
通讯作者：
Yoder MC
中科院分区：
文献类型：
--
作者：
Kim H;Huang L;Critser PJ;Yang Z;Chan RJ;Wang L;Carlesso N;Voytik-Harbin SL;Bernstein ID;Yoder MC
人脐带血（CB）富含循环内皮集落形成细胞（ECFC），其显示高增殖潜力和体内血管形成能力。由于Notch信号传导对子宫内胚胎血管形成至关重要，我们假设Notch通路激活可能增强体内培养的ECFC血管生成特性。用固定的嵌合Notch配体（Delta-like 1 ext-IgG）进行的体外ECFC刺激导致Notch调节的Hey 2和EphrinB 2的mRNA和蛋白水平显著增加，这通过添加γ-分泌酶抑制剂的处理来阻断。然而，Notch刺激的预处理在体外未能增强ECFC血管生成在体内。相比之下，ECFC与组成型表达Notch配体δ样1的OP 9-δ样1基质细胞的体内共植入导致增强的Notch活化的ECFC衍生的血管密度增加和血管面积扩大，这是OP 9对照基质植入未诱导的效果。这种Notch激活与暴露的ECFC中细胞凋亡减少有关。我们的结论是，Notch途径激活ECFC在体内通过共同植入的基质细胞表达δ样1促进血管生成和增强血管形成，通过减少植入的ECFC的细胞凋亡。
Human cord blood (CB) is enriched in circulating endothelial colony forming cells (ECFCs) that display high proliferative potential and in vivo vessel forming ability. Because Notch signaling is critical for embryonic blood vessel formation in utero, we hypothesized that Notch pathway activation may enhance cultured ECFC vasculogenic properties in vivo. In vitro ECFC stimulation with an immobilized chimeric Notch ligand (Delta-like1ext-IgG) led to significant increases in the mRNA and protein levels of Notch regulated Hey2 and EphrinB2 that were blocked by treatment with γ-secretase inhibitor addition. However, Notch stimulated preconditioning in vitro failed to enhance ECFC vasculogenesis in vivo. In contrast, in vivo co-implantation of ECFCs with OP9-Delta-like 1 stromal cells that constitutively expressed the Notch ligand delta-like 1 resulted in enhanced Notch activated ECFC-derived increased vessel density and enlarged vessel area in vivo, an effect not induced by OP9 control stromal implantation. This Notch activation was associated with diminished apoptosis in the exposed ECFC. We conclude that Notch pathway activation in ECFC in vivo via co-implanted stromal cells expressing delta-like 1 promotes vasculogenesis and augments blood vessel formation via diminishing apoptosis of the implanted ECFC.