Ieda Masaki, Tsuchihashi Takatoshi, Ivey Kathryn N, Ross Robert S, Hong Ting-Ting, Shaw Robin M, Srivastava Deepak
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, 94158, USA.
Dev Cell. 2009 Feb;16(2):233-44. doi: 10.1016/j.devcel.2008.12.007.
Growth and expansion of ventricular chambers is essential during heart development and is achieved by proliferation of cardiac progenitors. Adult cardiomyocytes, by contrast, achieve growth through hypertrophy rather than hyperplasia. Although epicardial-derived signals may contribute to the proliferative process in myocytes, the factors and cell types responsible for development of the ventricular myocardial thickness are unclear. Using a coculture system, we found that embryonic cardiac fibroblasts induced proliferation of cardiomyocytes, in contrast to adult cardiac fibroblasts that promoted myocyte hypertrophy. We identified fibronectin, collagen, and heparin-binding EGF-like growth factor as embryonic cardiac fibroblast-specific signals that collaboratively promoted cardiomyocyte proliferation in a paracrine fashion. Myocardial beta1-integrin was required for this proliferative response, and ventricular cardiomyocyte-specific deletion of beta1-integrin in mice resulted in reduced myocardial proliferation and impaired ventricular compaction. These findings reveal a previously unrecognized paracrine function of embryonic cardiac fibroblasts in regulating cardiomyocyte proliferation.
心室腔的生长和扩张在心脏发育过程中至关重要，这是通过心脏祖细胞的增殖来实现的。相比之下，成年心肌细胞通过肥大而非增生来实现生长。尽管心外膜衍生的信号可能有助于心肌细胞的增殖过程，但负责心室心肌厚度发育的因素和细胞类型尚不清楚。利用共培养系统，我们发现胚胎心脏成纤维细胞可诱导心肌细胞增殖，而成人心脏成纤维细胞则促进心肌细胞肥大。我们确定纤连蛋白、胶原蛋白和肝素结合表皮生长因子样生长因子是胚胎心脏成纤维细胞特异性信号，它们以旁分泌方式协同促进心肌细胞增殖。这种增殖反应需要心肌β1整合素，小鼠心室心肌细胞特异性缺失β1整合素会导致心肌增殖减少和心室致密化受损。这些发现揭示了胚胎心脏成纤维细胞在调节心肌细胞增殖方面以前未被认识的旁分泌功能。
