Sex-specific actions of estradiol and testosterone on human fibroblast and endothelial cell proliferation, bioenergetics, and vasculogenesis.
Sex-specific actions of estradiol and testosterone on human fibroblast and endothelial cell proliferation, bioenergetics, and vasculogenesis.
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雌二醇和睾酮对人成纤维细胞和内皮细胞增殖、生物能学和血管生成的性别特异性作用。
DOI：
10.1101/2023.07.23.550236
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Mondrinos,MarkJ
中科院分区：
文献类型：
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作者：
Martier,AshleyT;Maurice,YasminV;Conrad,KMichael;Mauvais-Jarvis,Franck;Mondrinos,MarkJ
性别特异性组织工程系统的发展进展受到了阻碍，缺乏研究工作，以确定性别特异性激素浓度对相关人类细胞类型的影响。在这里，我们研究了确定浓度的雌二醇（E2）和双氢睾酮（DHT）对原代人皮肤和肺成纤维细胞（HDF和HLF），以及来自女性（XX）和男性（XY）供体的人脐静脉内皮细胞（HUVEC）在2D扩增培养物和3D基质血管组织中的影响。在2D扩增培养中，性别匹配的E2和DHT刺激显著增加了所有测试细胞类型中的增殖指数、线粒体膜电位以及与生物能量学（Na+/K+ ATP酶、体细胞色素C）和有益应激反应（伴侣蛋白）相关的基因的表达。值得注意的是，交叉性激素刺激，在不存在E2的情况下对XX细胞进行DHT处理以及在不存在DHT的情况下对XY细胞进行E2刺激，会降低生物能能力并抑制细胞增殖。我们使用微工程3D血管发生测定来评估激素对组织尺度形态发生的影响。在XX组织中，与溶媒相比，E2增加了血管网络复杂性的指标。相反，与2D扩增培养的结果一致，与XY组织中的载体相比，E2有效抑制血管发生。DHT没有显着改变XX或XY组织中的血管发生，但增加了两种性别的非参与内皮细胞的数量。本研究为利用性激素刺激建立性别特异性培养体系提供了科学的理论基础和适用的方法。
Progress toward the development of sex-specific tissue engineered systems has been hampered by the lack of research efforts to define the effects of sex-specific hormone concentrations on relevant human cell types. Here, we investigated the effects of defined concentrations of estradiol (E2) and dihydrotestosterone (DHT) on primary human dermal and lung fibroblasts (HDF and HLF), and human umbilical vein endothelial cells (HUVEC) from female (XX) and male (XY) donors in both 2D expansion cultures and 3D stromal vascular tissues. Sex-matched E2 and DHT stimulation in 2D expansion cultures significantly increased the proliferation index, mitochondrial membrane potential, and the expression of genes associated with bioenergetics (Na+/K+ ATPase, somatic cytochrome C) and beneficial stress responses (chaperonin) in all cell types tested. Notably, cross sex hormone stimulation, i.e., DHT treatment of XX cells in the absence of E2 and E2 stimulation of XY cells in the absence of DHT, decreased bioenergetic capacity and inhibited cell proliferation. We used a microengineered 3D vasculogenesis assay to assess hormone effects on tissue scale morphogenesis. E2 increased metrics of vascular network complexity compared to vehicle in XX tissues. Conversely, and in line with results from 2D expansion cultures, E2 potently inhibited vasculogenesis compared to vehicle in XY tissues. DHT did not significantly alter vasculogenesis in XX or XY tissues but increased the number of non-participating endothelial cells in both sexes. This study establishes a scientific rationale and adaptable methods for using sex hormone stimulation to develop sex-specific culture systems.