Serotonin limits generation of chromaffin cells during adrenal organ development

Adrenal glands are the major organs releasing catecholamines and regulating our stress response. The mechanisms balancing generation of adrenergic chromaffin cells and protecting against neuroblastoma tumors are still enigmatic. Here we revealed that serotonin (5HT) controls the numbers of chromaffin cells by acting upon their immediate progenitor “bridge” cells via 5-hydroxytryptamine receptor 3A (HTR3A), and the aggressive HTR3Ahigh human neuroblastoma cell lines reduce proliferation in response to HTR3A-specific agonists. In embryos (in vivo), the physiological increase of 5HT caused a prolongation of the cell cycle in “bridge” progenitors leading to a smaller chromaffin population and changing the balance of hormones and behavioral patterns in adulthood. These behavioral effects and smaller adrenals were mirrored in the progeny of pregnant female mice subjected to experimental stress, suggesting a novel maternal-fetal link that controls developmental adaptations. Finally, these results corresponded to a size-distribution of adrenals found in wild rodents with different coping strategies. We isolated individual cells from AGM region or from the dissected intact adrenal glands with surrounding tissue from human embryos at post-conception weeks 5, 6, and 7 and subjected them to single-cell transcriptomics sequencing using 10x Chromium approach.

肾上腺是分泌儿茶酚胺、调控机体应激反应的关键器官。调控肾上腺素能嗜铬细胞生成并抑制神经母细胞瘤发生的机制仍不明晰。本研究揭示，血清素（serotonin, 5HT）可通过5-羟色胺3A型受体（5-hydroxytryptamine receptor 3A, HTR3A）作用于嗜铬细胞的直接祖细胞——“桥梁”细胞，以此调控嗜铬细胞的数量；高表达HTR3A的侵袭性人神经母细胞瘤细胞系，在HTR3A特异性激动剂处理后增殖能力显著下降。在活体胚胎中，血清素的生理性升高会延长“桥梁”祖细胞的细胞周期，进而导致嗜铬细胞群体规模缩小，并改变成年个体的激素平衡与行为模式。经实验性应激处理的孕鼠后代，同样表现出上述行为异常与肾上腺体积减小的表型，这提示存在一条调控发育适应性的全新母胎信号通路。最后，该研究结果与不同应对策略的野生啮齿类动物的肾上腺体积分布特征相吻合。本研究从受孕后第5、6、7周的人类胚胎的主动脉-性腺-中肾（AGM）区，或完整剥离的肾上腺及其周围组织中分离出单个细胞，并采用10x Chromium平台开展单细胞转录组测序。