Nunes Sara S, Feric Nicole, Pahnke Aric, Miklas Jason W, Li Mark, Coles John, Gagliardi Mark, Keller Gordon, Radisic Milica
Toronto General Research Institute, University Health Network, 101 College Street Toronto, Ontario, Canada M5G 1L7.
Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, 101 College Street, MaRS Third Floor, Room 902, Toronto, Ontario, Canada M5G 1L7.
ACS Biomater Sci Eng. 2017 Sep 11;3(9):1911-1921. doi: 10.1021/acsbiomaterials.5b00496. Epub 2016 May 10.
Animal models have been instrumental in providing insight into the molecular basis of disease. While such information has been successfully applied to the study of human disease, this translation would be significantly strengthened by the availability of models based on human cells. This would be particularly important for cardiovascular disease, as the physiology of human cardiomyocytes (CMs) differs significantly from rodents. Here, we have generated a three-dimensional human engineered cardiac tissue, termed biowire, from human embryonic stem cell-derived CMs to investigate the effects of chronic (7 day) treatment with isoproterenol, endothelin-1, or angiotensin II. We show that biowires chronically treated with either isoproterenol, endothelin-1, or angiotensin II have disrupted myofibril alignment and significantly reduced force of contraction. Isoproterenol-treated biowires have upregulated brain natriuretic peptide and atrial natriuretic peptide gene expression. Endothelin-1 and angiotensin II-treated biowires demonstrated a significantly increased cell size. Endothelin-1-treated biowires exhibited increased cardiac troponin secretion into the culture media. This demonstrates that human biowires treated for 7 days with isoproterenol, angiotensin II, or endothelin-1 exhibit some changes compatible with hypertrophic cardiomyopathy.
动物模型在深入了解疾病的分子基础方面发挥了重要作用。虽然这些信息已成功应用于人类疾病研究，但基于人类细胞的模型若能问世，将极大地增强这种转化研究。这对于心血管疾病尤为重要，因为人类心肌细胞（CMs）的生理学与啮齿动物有显著差异。在此，我们利用人类胚胎干细胞衍生的CMs构建了一种三维人类工程化心脏组织，称为生物线，以研究异丙肾上腺素、内皮素-1或血管紧张素II进行慢性（7天）处理的效果。我们发现，用异丙肾上腺素、内皮素-1或血管紧张素II进行慢性处理的生物线，其肌原纤维排列紊乱，收缩力显著降低。用异丙肾上腺素处理的生物线，脑钠肽和心房钠尿肽基因表达上调。用内皮素-1和血管紧张素II处理的生物线，细胞大小显著增加。用内皮素-1处理的生物线，心肌肌钙蛋白分泌到培养基中的量增加。这表明，用异丙肾上腺素、血管紧张素II或内皮素-1处理7天的人类生物线表现出一些与肥厚型心肌病相符的变化。
