Lepilina Alexandra, Coon Ashley N, Kikuchi Kazu, Holdway Jennifer E, Roberts Richard W, Burns C Geoffrey, Poss Kenneth D
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Cell. 2006 Nov 3;127(3):607-19. doi: 10.1016/j.cell.2006.08.052.
Zebrafish possess a unique yet poorly understood capacity for cardiac regeneration. Here, we show that regeneration proceeds through two coordinated stages following resection of the ventricular apex. First a blastema is formed, comprised of progenitor cells that express precardiac markers, undergo differentiation, and proliferate. Second, epicardial tissue surrounding both cardiac chambers induces developmental markers and rapidly expands, creating a new epithelial cover for the exposed myocardium. A subpopulation of these epicardial cells undergoes epithelial-to-mesenchymal transition (EMT), invades the wound, and provides new vasculature to regenerating muscle. During regeneration, the ligand fgf17b is induced in myocardium, while receptors fgfr2 and fgfr4 are induced in adjacent epicardial-derived cells. When fibroblast growth factors (Fgf) signaling is experimentally blocked by expression of a dominant-negative Fgf receptor, epicardial EMT and coronary neovascularization fail, prematurely arresting regeneration. Our findings reveal injury responses by myocardial and epicardial tissues that collaborate in an Fgf-dependent manner to achieve cardiac regeneration.
斑马鱼具有独特但尚未被充分理解的心脏再生能力。在此，我们表明，在心室尖切除后，再生过程通过两个协调的阶段进行。首先形成一个芽基，由表达心前标记物、经历分化并增殖的祖细胞组成。其次，围绕两个心腔的心外膜组织诱导发育标记物并迅速扩张，为暴露的心肌创造一个新的上皮覆盖层。这些心外膜细胞的一个亚群经历上皮-间充质转化（EMT），侵入伤口，并为再生肌肉提供新的血管。在再生过程中，配体fgf17b在心肌中被诱导，而受体fgfr2和fgfr4在相邻的心外膜衍生细胞中被诱导。当成纤维细胞生长因子（Fgf）信号通过显性负性Fgf受体的表达被实验性阻断时，心外膜EMT和冠状新血管形成失败，再生过早停止。我们的发现揭示了心肌和心外膜组织的损伤反应，它们以Fgf依赖的方式协同作用以实现心脏再生。
