Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.
Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.
Circulation. 2021 Apr 20;143(16):1614-1628. doi: 10.1161/CIRCULATIONAHA.120.051921. Epub 2021 Mar 8.
Despite in-depth knowledge of the molecular mechanisms controlling embryonic heart development, little is known about the signals governing postnatal maturation of the human heart.
Single-nucleus RNA sequencing of 54 140 nuclei from 9 human donors was used to profile transcriptional changes in diverse cardiac cell types during maturation from fetal stages to adulthood. Bulk RNA sequencing and the Assay for Transposase-Accessible Chromatin using sequencing were used to further validate transcriptional changes and to profile alterations in the chromatin accessibility landscape in purified cardiomyocyte nuclei from 21 human donors. Functional validation studies of sex steroids implicated in cardiac maturation were performed in human pluripotent stem cell-derived cardiac organoids and mice.
Our data identify the progesterone receptor as a key mediator of sex-dependent transcriptional programs during cardiomyocyte maturation. Functional validation studies in human cardiac organoids and mice demonstrate that the progesterone receptor drives sex-specific metabolic programs and maturation of cardiac contractile properties.
These data provide a blueprint for understanding human heart maturation in both sexes and reveal an important role for the progesterone receptor in human heart development.
尽管我们对控制胚胎心脏发育的分子机制有深入的了解，但对于控制人类心脏出生后成熟的信号知之甚少。
使用单细胞 RNA 测序技术对 9 名供体的 54140 个核进行测序，以分析从胎儿期到成年期不同心脏细胞类型在成熟过程中的转录变化。使用批量 RNA 测序和使用测序的转座酶可及染色质分析进一步验证转录变化，并对 21 名供体纯化的心肌细胞核中染色质可及性图谱的改变进行分析。对涉及心脏成熟的性激素的功能验证研究是在人多能干细胞来源的心脏类器官和小鼠中进行的。
我们的数据确定孕激素受体是心肌细胞成熟过程中性别依赖转录程序的关键介质。在人心脏类器官和小鼠中的功能验证研究表明，孕激素受体驱动心脏收缩特性的性别特异性代谢程序和成熟。
这些数据为理解两性人类心脏成熟提供了蓝图，并揭示了孕激素受体在人类心脏发育中的重要作用。
