Imperial College London, National Heart and Lung Institute, London, UK.
Imperial College London, National Heart and Lung Institute, London, UK King Fahad Cardiac Center, King Saud University, Riyadh, Saudi Arabia.
Cardiovasc Res. 2015 Mar 1;105(3):260-70. doi: 10.1093/cvr/cvu264. Epub 2015 Jan 5.
Crosstalk between cardiomyocytes and fibroblasts in physiological conditions and during disease remains poorly defined. Previous studies have shown that fibroblasts and myocytes interact via paracrine communication, but several experimental confounding factors, including the use of immature myocytes and the induction of alpha-smooth muscle actin (α-SMA) expression in fibroblasts by prolonged culture, have hindered our understanding of this phenomenon. We hypothesize that fibroblasts and myofibroblasts differentially affect cardiomyocytes viability, volume, and Ca(2+) handling via soluble mediators. More specifically here: (i) we compare the effects of freshly isolated fibroblasts and cultured fibroblasts from normal rat hearts on adult cardiomyocytes; (ii) we compare the effects of (freshly isolated) normal fibroblasts and myofibroblasts from pressure-overloaded hearts; and (iii) we study the contribution of TGF-β and the importance of the crosstalk between the two cell types.
We used co-culture methods and conditioned medium to investigate paracrine interaction between fibroblasts and cardiomyocytes. All fibroblast types reduce cardiomyocyte viability and increase cardiomyocyte volume but α-SMA-negative fibroblasts increase cardiomyocyte Ca(2+) transient amplitude, whereas cultured fibroblasts and myofibroblasts from pressure-overloaded hearts decrease Ca(2+) transient amplitude. In turn, cardiomyocytes release soluble mediators that affect fibroblast proliferation. Using SB431542 to block TGF-β type 1 receptors, we determined that TGF-β directly causes cardiomyocyte hypertrophy and participates in bi-directional regulatory signalling between fibroblasts and cardiomyocytes.
Fibroblasts have different roles during physiology and disease in regulating myocardial function via soluble mediators. A crosstalk between fibroblasts and cardiomyocytes, controlled by TGF-β, is crucial in this interaction.
在生理条件下和疾病期间，心肌细胞和成纤维细胞之间的串扰仍然定义不明确。先前的研究表明，成纤维细胞和心肌细胞通过旁分泌通讯相互作用，但几个实验混杂因素，包括使用不成熟的心肌细胞和通过延长培养诱导成纤维细胞中α-平滑肌肌动蛋白（α-SMA）的表达，阻碍了我们对这一现象的理解。我们假设成纤维细胞和成纤维肌细胞通过可溶性介质差异地影响心肌细胞的活力、体积和 Ca(2+)处理。更具体地说：（i）我们比较来自正常大鼠心脏的新鲜分离的成纤维细胞和培养的成纤维细胞对成年心肌细胞的影响；（ii）我们比较（新鲜分离的）来自压力超负荷心脏的正常成纤维细胞和成纤维肌细胞的影响；（iii）我们研究 TGF-β的贡献和两种细胞类型之间串扰的重要性。
我们使用共培养方法和条件培养基研究成纤维细胞和心肌细胞之间的旁分泌相互作用。所有类型的成纤维细胞均降低心肌细胞活力并增加心肌细胞体积，但α-SMA-阴性成纤维细胞增加心肌细胞 Ca(2+)瞬变幅度，而培养的成纤维细胞和成纤维肌细胞来自压力超负荷心脏则降低 Ca(2+)瞬变幅度。反过来，心肌细胞释放影响成纤维细胞增殖的可溶性介质。使用 SB431542 阻断 TGF-β 1 型受体，我们确定 TGF-β 直接引起心肌细胞肥大，并参与成纤维细胞和心肌细胞之间的双向调节信号转导。
成纤维细胞通过可溶性介质在生理和疾病期间具有不同的作用，以调节心肌功能。成纤维细胞和心肌细胞之间的串扰，由 TGF-β 控制，在这种相互作用中至关重要。
