NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China.
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
Am J Reprod Immunol. 2022 Sep;88(3):e13540. doi: 10.1111/aji.13540. Epub 2022 Apr 18.
During early pregnancy, a large number of CD56 natural killer cells (NKs) are accumulated in the decidua; unlike peripheral and cord blood NK cells (pNK and cNK), these decidual NK cells (dNK) display a great capacity to secrete a series of angiogenic/vascular factors, which are essential for placental development. However, the mechanism underlying the formation of dNK cells with an angiogenic phenotype remains unclear.
First, we compared the difference between dNK and cNK/pNK cells in terms of the expression of CD56 and VEGF, and the regulation of the tube formation. The effect of cAMP on the differentiation of NK cells was evaluated by its analog and inhibitor stimulation. We further analyzed the differences in the phenotype of dNK cells and the expression of VEGF in dNK cells from normal pregnancies and miscarriages.
Different from cNK and pNK, dNK cells displayed high expression of CD56 and VEGF. And dNK cells showed a higher capacity of inducing tube formation of HUVEC by trophoblast. Meanwhile, we observed that cAMP-analogue increased the percentage of CD56 NK population in cNK cells with up-regulated VEGF secretion and tube formation of HUVEC by trophoblast, which could be inhibited by pretreatment with VEGFR neutralizing antibody. Similar changes occurred when co-culturing cNK cells with DSCs but not ESCs. Interestingly, the inhibitor of cAMP signaling (Metadoxine, META) could significantly inhibit the upregulation of VEGF in cNK cells by DSCs. Furthermore, DSCs could secret much more cAMP than ESCs. Notably, decreased CD56 NK population and VEGF secretion by dNK were related to pregnancy loss.
These findings suggest that dNK cells display an angiogenic phenotype that can be induced by decidualized cAMP signaling. Our study indicates the significance of decidualization-derived cAMP in regulating angiogenesis of decidual NKs and reveals complex crosstalk between different cell types in a critical period during early pregnancy.
在早孕期间，大量的 CD56 自然杀伤细胞（NK 细胞）积聚在蜕膜中；与外周血和脐血 NK 细胞（pNK 和 cNK）不同，这些蜕膜 NK 细胞（dNK）具有分泌一系列血管生成/血管因子的巨大能力，这对于胎盘发育至关重要。然而，形成具有血管生成表型的 dNK 细胞的机制尚不清楚。
首先，我们比较了 dNK 和 cNK/pNK 细胞在 CD56 和 VEGF 表达以及管形成的调节方面的差异。通过其类似物和抑制剂刺激来评估 cAMP 对 NK 细胞分化的影响。我们进一步分析了正常妊娠和流产中 dNK 细胞的表型差异以及 dNK 细胞中 VEGF 的表达。
与 cNK 和 pNK 不同，dNK 细胞高表达 CD56 和 VEGF。并且 dNK 细胞显示出更高的诱导滋养层形成 HUVEC 管形成的能力。同时，我们观察到 cAMP 类似物增加了 cNK 细胞中 CD56 NK 群体的百分比，同时增加了 VEGF 的分泌和滋养层形成的 HUVEC 管形成，这可以通过用 VEGFR 中和抗体预处理来抑制。当共培养 cNK 细胞与 DSCs 而不是 ESCs 时，会发生类似的变化。有趣的是，cAMP 信号转导的抑制剂（Metadoxine，META）可显著抑制 DSCs 对 cNK 细胞中 VEGF 的上调。此外，DSCs 分泌的 cAMP 明显多于 ESCs。值得注意的是，dNK 中 CD56 NK 群体和 VEGF 分泌的减少与妊娠丢失有关。
这些发现表明，dNK 细胞显示出一种血管生成表型，可通过蜕膜化的 cAMP 信号诱导。我们的研究表明，在早期妊娠的关键时期，蜕膜化衍生的 cAMP 在调节蜕膜 NK 细胞的血管生成方面具有重要意义，并揭示了不同细胞类型之间的复杂串扰。
