Marsh Spencer, Raudat Madeline, Lefeber Bethany, Herndon Laura Beth, Herbert Howard, McCallum Laura, Simionescu Agneta
Department of Bioengineering, Clemson University, 507 Rhodes Research Center, Clemson, SC 29654, USA.
J Mech Med Biol. 2021 Aug;21(6). doi: 10.1142/s0219519421500470. Epub 2021 Jul 15.
In clinical diabetic cardiomyopathy, hyperglycemia and dyslipidemia induce tissue injury, activation of cardiac fibroblasts and interstitial and perivascular fibrosis. Myofibroblasts repair the injured tissue by increasing collagen deposition in the cardiac interstitium and suppressing the activity of matrix metalloproteinases. The goal of this study was to find an ideal model to mimic the effect of high glucose concentration on human cardiac fibroblast activation. The profibrotic role of the transforming growth factor-β (TGF-β) and the protective modulation of nitric oxide were examined in two-dimensional and three-dimensional cell culture models, as well as tissue engineering models, that involved use of cardiac fibroblasts cultured within myocardial matrix scaffolds mounted in a bioreactor that delivered biochemical and mechanical stimuli. Results showed that high glucose levels were potent pro-fibrotic stimuli, In addition, high glucose levels in concert with TGF-β constituted very strong signals that induced human cardiac fibroblast activation. Cardiac fibroblasts cultured within decellularized myocardial scaffolds and exposed to biochemical and mechanical stimuli represented an adequate model for this pathology, In conclusion, the bioreactor platform was instrumental in establishing an in vitro model of early fibrosis; this platform could be used to test the effects of various agents targeted to mitigate the fibrotic processes.
在临床糖尿病性心肌病中，高血糖和血脂异常会导致组织损伤、心脏成纤维细胞活化以及间质和血管周围纤维化。肌成纤维细胞通过增加心脏间质中的胶原蛋白沉积并抑制基质金属蛋白酶的活性来修复受损组织。本研究的目的是找到一个理想模型来模拟高糖浓度对人心脏成纤维细胞活化的影响。在二维和三维细胞培养模型以及组织工程模型中，研究了转化生长因子-β（TGF-β）的促纤维化作用和一氧化氮的保护调节作用，这些模型涉及使用培养在安装于生物反应器中的心肌基质支架内的心脏成纤维细胞，该生物反应器可传递生化和机械刺激。结果表明，高糖水平是强大的促纤维化刺激因素。此外，高糖水平与TGF-β协同构成了诱导人心脏成纤维细胞活化的非常强烈的信号。在脱细胞心肌支架内培养并暴露于生化和机械刺激的心脏成纤维细胞代表了这种病理状态的合适模型。总之，生物反应器平台有助于建立早期纤维化的体外模型；该平台可用于测试各种旨在减轻纤维化过程的药物的效果。
