Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, Leuven, 3000, Belgium.
Cardiovascular Imaging and Dynamics, Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, Leuven, 3000, Belgium.
Sci Rep. 2017 Sep 7;7(1):10801. doi: 10.1038/s41598-017-09790-1.
Fibroblast (Fb) differentiation and interstitial fibrosis contribute to cardiac remodeling and loss of function after myocardial infarction (MI). We investigated regional presence and regulation of fibrosis in a pig MI model. In vivo analysis of regional function and perfusion defined three regions: the scar, the myocardium adjacent to the scar (MI, reduced function, reduced perfusion reserve), and the remote myocardium (MI, minimal functional deficit, maintained perfusion). Interstitial and perivascular fibrosis, and increase of collagen type I, was only observed in the MI. Fb activated protein-alpha (FAP-α) was enriched in MI compared to MI. TGF-β1, which triggers Fb differentiation, was upregulated in both MI and MI, whereas lysyl oxidase, a regulator of collagen cross-linking, and the proteoglycans decorin and biglycan were only increased in the MI. Fb isolated and cultured for 4 days had myoFb characteristics with little difference between MI and MI, although RNA sequencing revealed differences in gene expression profiles. Fbs from all regions maintained proliferative capacity, and induced contraction of 3-D collagen matrices but scar myoFb was more effective. These data suggest that after MI, signaling through TGF-β1, possibly related to increased mechanical load, drives Fb activation throughout the left ventricle while regional signaling determines further maturation and extracellular matrix remodeling after MI.
成纤维细胞（Fb）分化和间质纤维化导致心肌梗死后心脏重构和功能丧失。我们研究了猪心肌梗死模型中纤维化的局部存在和调节。对局部功能和灌注的体内分析定义了三个区域：疤痕、疤痕相邻的心肌（MI，功能降低，灌注储备减少）和远程心肌（MI，功能缺损最小，灌注保持）。只有在 MI 中才观察到间质和血管周围纤维化以及胶原 I 型的增加。与 MI 相比，Fb 激活蛋白-α（FAP-α）在 MI 中更为丰富。触发 Fb 分化的 TGF-β1 在 MI 和 MI 中均上调，而赖氨酰氧化酶（胶原蛋白交联的调节剂）和蛋白聚糖 decorin 和 biglycan 仅在 MI 中增加。分离并培养 4 天的 Fb 具有肌成纤维细胞的特征，尽管 RNA 测序显示 MI 和 MI 之间的基因表达谱存在差异。所有区域的 Fb 均保持增殖能力，并诱导 3-D 胶原基质收缩，但疤痕肌成纤维细胞更有效。这些数据表明，在 MI 后，通过 TGF-β1 的信号转导可能与增加的机械负荷有关，在左心室中驱动 Fb 激活，而局部信号转导决定 MI 后进一步的成熟和细胞外基质重塑。
