Placental Inflammation Leads to Abnormal Embryonic Heart Development.
Placental Inflammation Leads to Abnormal Embryonic Heart Development.
复制标题
胎盘炎症导致胚胎心脏发育异常。
DOI：
10.1161/circulationaha.122.061934
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发表时间：
2023-03-21
期刊：
影响因子：
37.8
通讯作者：
Nadkarni, Suchita
中科院分区：
文献类型：
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作者：
Ward, Eleanor J.;Bert, Serena;Fanti, Silvia;Malone, Kerri M.;Maughan, Robert T.;Gkantsinikoudi, Christina;Prin, Fabrice;Volpato, Lia Karina;Piovezan, Anna Paula;Graham, Gerard J.;Dufton, Neil P.;Perretti, Mauro;Marelli-Berg, Federica M.;Nadkarni, Suchita
胎盘心脏发育和胚胎心脏发育是并行发生的，并且有人提出这些器官在妊娠期间存在相互调节作用。胎盘发育不良与先天性心脏病有关，先天性心脏病是婴儿死亡的一个重要原因。然而，胎盘发育改变导致先天性心脏病的机制仍未明确。
在这项研究中，我们在定时交配的小鼠妊娠关键阶段（胚胎第4.5天和第7.5天）通过抗体清除母体循环中的中性粒细胞，使用一种体内中性粒细胞驱动的胎盘炎症模型。在胚胎第14.5天处死怀孕小鼠以评估胎盘和胚胎心脏的发育。我们结合使用流式细胞术、组织学和大量RNA测序来评估胎盘免疫细胞组成和组织结构。我们还使用流式细胞术和单细胞测序来评估胚胎第14.5天的胚胎心脏免疫细胞，并使用组织学和基因分析来研究胚胎心脏结构和发育。在某些情况下，在出生后第5天和第28天处死后代，以通过超声心动图评估免疫细胞、结构和心脏功能的任何出生后变化。
在本研究中，我们表明中性粒细胞驱动的胎盘炎症导致胎盘发育不良和屏障功能丧失。因此，源自母体的胎盘炎性单核细胞能够迁移到胚胎心脏，并改变驻留心脏巨噬细胞的正常组成和心脏组织结构。这种心脏损伤持续到出生后的生活中，阻碍正常的组织结构和功能。最后，我们表明减轻胎盘炎症可以预防这种胎儿心脏缺陷，并足以促进出生后生活中的正常心脏功能。
综上所述，这些观察结果提供了一种机制范例，即妊娠期间中性粒细胞驱动的炎症可因胎盘发育不良而直接阻碍正常的胚胎心脏发育，这对成年后的心脏功能具有重大影响。
Placental heart development and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor placentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain unresolved. In this study, we use an in vivo neutrophil-driven placental inflammation model through antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy: embryonic days 4.5 and 7.5. Pregnant mice were culled at embryonic day 14.5 to assess placental and embryonic heart development. A combination of flow cytometry, histology, and bulk RNA sequencing was used to assess placental immune cell composition and tissue architecture. We also used flow cytometry and single-cell sequencing to assess embryonic cardiac immune cells at embryonic day 14.5 and histology and gene analyses to investigate embryonic heart structure and development. In some cases, offspring were culled at postnatal days 5 and 28 to assess any postnatal cardiac changes in immune cells, structure, and cardiac function, as measured by echocardiography. In the present study, we show that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. Consequently, placental inflammatory monocytes of maternal origin become capable of migration to the embryonic heart and alter the normal composition of resident cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Last, we show that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life. Taken together, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development, which has major implications on cardiac function into adult life.