呼吸内胚层，第二生心区与小鼠胚胎心脏流出道远端的形态发生
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摘要
有效体循环和肺循环的建立有赖于心脏腔室正常的形态发生和分隔。已知在原始心管形成后,第二生心区的心脏前体细胞通过心背系膜迁移入心脏,参与形成流出道、右心室、部分心房和房间隔(含背侧间充质突),并且聚集于主动脉干和肺动脉干。转基因或基因敲除小鼠胚胎的研究表明：条件性敲除前肠内胚层的某些相关转录因子或者信号分子导致流出道分隔畸形。提示前肠内胚层在流出道和第二生心区的正常发育调节中扮演重要角色。目前有关前肠内胚层与心脏发育关系的研究主要限于对两栖类、鸡胚的体外观察及对敲除内胚层相关基因小鼠的观察,对正常小鼠前肠内胚层发育与心发生的形态学关系及机制鲜见被报道。Sonic hedgehog (SHH)信号通路参与心血管系统多个器官的发育和分化调控。SHH信号分子必须与其受体结合才能发挥生物学效应。研究表明前肠内胚层是SHH信号分子源之一。在心脏前体细胞分化过程中,条件性敲除前肠内胚层细胞的SHH基因导致出现流出道畸形如永存动脉干、大动脉转位等,以及心房和房室分隔的异常。然而SHH信号通路成员在前肠内胚层发育中的表达特点,及与第二生心区和流出道发育的形态学关系鲜见被描述。为了深入了解前肠内胚层细胞与周围Islet-1(Isl-1)阳性的第二生心区细胞间相互作用的机制,我们观察了小鼠胚胎心脏流出道正常发育过程中,喉-气管沟(前肠内胚层来源)与第二生心区发育的形态学关系,以及SHH信号通路主要受体Patchedl (Ptcl)、Patched2(Ptc2)和Smoothened (Smo)在上述结构发育中的表达模式。结果显示一个位于前肠腹侧的Isl-1阳性细胞区与呼吸内胚层(喉-气管沟)的发育紧密耦连,并且Isl-1阳性细胞围绕发育中的喉-气管沟形成独特的分布模式。我们把围绕喉-气管沟发育的前肠腹侧Isl-1阳性细胞区简称为呼吸内胚层相关Isl-1阳性细胞区(Pulmonary endoderm-associated Isl-1positive field, PE-Isl-1F)。多项研究已经证实：前肠腹侧的Isl-1阳性间充质参与心脏形态发生,是第二生心区细胞的亚群。因此PE-Isl-1F应当属于第二生心区。在PE-Isl-1F发育过程中,SHH信号受体Ptcl和Ptc2仅表达于发育中的呼吸内胚层=PE-Isl-1F与发育中喉-气管沟位置上的接近性可能是PE-Isl-1F心前体细胞向心谱系细胞分化所必需的。PE-Isl-1F的Is1-1阳性细胞除了参与心包内主动脉和肺动脉干侧壁的形成,还突入动脉囊腔内,与流出道心内膜垫远侧端融合,形成暂时性的主-肺动脉隔。我们的研究结果为内胚层与第二生心区的相互作用提供了形态学上的证据,也支持了Hoffmann et al关于呼吸内胚层诱导有效体循环和肺循环建立所需心脏结构形成的假设。
第一部分呼吸内胚层与呼吸内胚层相关第二生心区的发育耦联
背景与目的：原始心管形成后,被Is1-1标记的第二生心区心前体细胞向流出道和右心室迁移,参与心脏动脉端形成。条件性敲除前肠内胚层的某些相关转录因子或者信号分子导致流出道畸形,提示前肠内胚层在流出道和第二生心区的正常发育调节中扮演重要角色。为了深入了解该类流出道畸形发生的机制,我们观察了正常小鼠胚胎心脏流出道发育过程中,喉-气管沟(前肠内胚层分化而成)与周围第二生心区Is1-1阳性间充质细胞发育的形态学关系。
研究方法：分别用Isl-1标记第二生心区细胞、Foxa2标记内胚层细胞、Laminin标记基膜、E-cadherin标记上皮极性、MHC标记心肌细胞和α-SMA标记平滑肌细胞,对胚胎发育第9-13天鼠胚标本连续切片进行免疫组化染色或者荧光免疫双标染色。
研究结果：胚胎发育第9天,前肠腹侧壁Is1-1阳性的内胚层局部增厚,提示呼吸内胚层分化开始。胚胎发育第9.5天,喉-气管沟发育一经开始,Isl-1阳性细胞就开始出现在喉-气管沟内胚层周围的基质,我们称之为呼吸内胚层相关Is1-1阳性细胞区(PE-Isl-1F)。胚胎发育第10-12天,随着喉-气管沟向动脉囊背侧壁方向生长延伸,PE-Isl-1F的Isl-1阳性细胞的数量增多,Is1-1阳性细胞紧紧围绕呼吸内胚层呈特征性锥体形结构发布,其宽的底边紧贴前肠底壁；腹侧端突入动脉囊腔。喉-气管沟发育过程中,从胚胎发育第10.5天到第12天在喉-气管沟末端总能看到一条实心内胚层细胞索。喉-气管沟及其实心细胞索的呼吸内胚层位于PE-Isl-1F的Isl-1阳性锥体形结构的中心。在喉-气管沟和PE-Isl-1F发育过程中,尤其在胚胎发育第11天,某些部位的内胚层基膜模糊不清或者中断,同时伴有一些呼吸内胚层细胞失去Foxa2表达和上皮极性。胚胎发育第13天,流出道水平的前肠完成分隔、形成气管,内胚层细胞索消失,PE-Isl-1F的Isl-1表达强度减弱。
研究结论：1.呼吸内胚层的分化发育与PE-Isl-1F的Isl-1阳性间充质细胞的发育聚集密切耦联。2.呼吸内胚层诱导PE-Isl-1F形成独特的分布模式。3.上皮-间充质转化与呼吸内胚层和PE-Isl-1F耦联发育有关。
第二部分SHH受体在呼吸内胚层和呼吸内胚层相关第二生心区的独特表达
背景与目的：前肠内胚层是SHH信号分子源之一。基因消融或组织特异性敲除内胚层SHH基因或Smo基因导致多种鼠胚流出道发育畸形,但此类流出道畸形产生的原因和机制并未完全阐明。已知在原始心管形成后,第二生心区的心脏前体细胞通过心背系膜迁移入心脏,参与形成流出道和右心室。为了明确SHH信号通路、前肠内胚层和第二生心区在胚胎心脏发育中的形态学关系,我们观察了SHH受体Ptc1、Ptc2和Smo在呼吸内胚层和PE-Isl-1F发育过程中的表达模式。
研究方法：对胚胎发育第9-13天鼠胚标本连续切片进行Ptc1/Isl-1、Ptc2/Isl-1和Smo/Isl-1的荧光免疫双标染色。
研究结果：胚胎发育第9天,Ptc1和Ptc2开始仅表达于呼吸内胚层。随着呼吸内胚层向腹侧生长形成喉-气管沟,较强的Ptc1和Ptc2主要局限于喉-气管沟的内胚层表达直到胚胎发育第12天。从胚胎发育第9天到第13天,Smo在胚胎各胚层均广泛表达。呼吸内胚层周围的PE-Isl-1F间充质同时表达Isl-1和Smo。
研究结论：1.SHH信号通路以自分泌或旁分泌模式参与呼吸内胚层发育和喉-气管沟及实心细胞索的形成。2.SHH信号通路与呼吸内胚层周围PE-Isl-1F形成有关。
第三部分呼吸内胚层相关第二生心区与小鼠胚胎心脏流出道远端的形态发生
背景与目的：目前流出道远端的形态发生和分隔仍存争议。已知原始心管形成后,第二生心区向流出道添加心肌细胞和平滑肌细胞,参与流出道发育。在该部分,我们观察了小鼠胚胎心脏流出道正常发育过程中,呼吸内胚层相关Isl-1阳性细胞区(PE-Isl-1F)与心包内动脉干形态发生的关系。
研究方法：分别用Isl-1标记第二生心区细胞、MHC标记心肌细胞和α-SMA标记平滑肌细胞,对胚胎发育第9-13天鼠胚标本连续切片进行免疫组化染色或者荧光免疫双标染色。
研究结果：从胚胎发育第10天起,围绕喉-气管沟发育的PE-Isl-1F腹侧末端突入动脉囊,形成明显的“突起”结构。胚胎发育第11.5天,尽管动脉囊和流出道尚未分隔,但分别在第四弓动脉和第六弓动脉水平可见PE-Isl-1F延伸入流出道头端壁和尾端壁,形成流出道远端管壁上的Isl-1阳性细胞团,向未来的心包内主动脉和肺动脉干侧壁分化。胚胎发育第12天,PE-Isl-1F末端“突起”逐渐失去Isl-1表达,获得较强α-SMA表达。尔后α-SMA阳性的PE-Isl-1F“突起”与α-SMA阳性的流出道远端融合,形成暂时性的主-肺动脉隔,将动脉囊分隔为心包内主动脉和肺动脉。胚胎发育第13天,心包内主动脉和肺动脉管壁出现α-SMA阳性平滑肌层,两者间的主-肺动脉隔消失。
研究结论：呼吸内胚层相关第二生心区参与心包内大动脉的形态发生和分隔。
The establishment of efficient systemic and pulmonary circulation relies on the normal morphogenesis and septation of the heart chambers. It has been demonstrated that the cardiac progenitor cells derived from the second heart field (SHF) migrate through dorsal mesocardium to form outflow tract (OFT), right ventricle, part of the atria, and the atrial septum, including the dorsal mesenchymal protrusion, and to populate the aorta and pulmonary trunk. The data from the transgenic mice and gene knockout mouse embryos have revealed that conditional deletion of transcription factors or signal proteins from the foregut endoderm result in the malformation of OFT septation, suggesting that foregut endoderm plays roles in regulation of normal development of OFT and SHF. Major insights on the relationship of foregut endoderm development with the heart development have been gained from the studies of a number of vertebrate and invertebrate models, including mouse, chick, amphibians, et al, via the culture in vitro or the deletion of endoderm genes in vivo. However, in wide-type embryonic mouse, the morphological relationship in the development of foregut endoderm and embryonic heart and the mechanism underlying the interaction between them are seldom described. Sonic hedgehog (SHH) signaling pathway coordinates multiple aspects of cardiovascular growth and development. As a secreted ligand, SHH can only function properly by binding to its receptors, including patchedl (Ptcl), patched2(Ptc2) and smoothened (Smo). Foregut endoderm has been regarded as one of the sources of SHH ligand and conditional abrogation of SHH signaling in foregut endoderm during the cardiac progenitor cell specification leads to the OFT malformation, including persistent truncus arterious, transposition of great arteries, etc. and the atrial and atrioventricular septal defect as well. However, the morphological relationship of expression of SHH signaling pathway members in developing foregut endoderm with development of surrounding SHF and OFT is seldom described. In order to get insight into the mechanism underlying the interaction between foregut endoderm and surrounding Islet-1(Isl-1) positive second heart field mesenchyme, we investigated the morphological relationship of developing trachea groove with SHF during normal OFT development of the mouse embryonic heart, and the expression patterns of Ptc1, Ptc2and Smo, critical receptors in SHH signaling pathway. The results demonstrated that the development of a subset of Isl-1positive field ventral to the foregut is closely coupled with pulmonary endoderm or tracheal groove, and the Isl-1positive cells surrounding the trachea groove is distributed in a special pattern. Because several lines of evidence have demonstrated that the Isl-1positive mesenchyme beneath the foregut floor takes part in the morphogenesis of the heart and therefore is considered to be a subset of the second heart field, we dubbed the subset of Isl-1positive field ventral to the foregut as pulmonary endoderm-associated Isl-1field (PE-Isl-1F). During PE-Isl-1F development, the SHH receptors Ptcl and Ptc2are exclusively expressed in the developing pulmonary endoderm. Close proximity of PE-Isl-1F to the developing trachea groove might be required for and facilitate the specification of the progenitor cells in PE-Isl-1F into cardiac lineage. In addition to taking part in the formation of the lateral walls of the intrapericardial aorta and pulmonary trunk, Isl-1positive cells of PE-Isl-1F surrounding the trachea groove protrude into the aortic sac, together with the distal end of the outflow trunk cushions, to form the transient aortic-pulmonary septum (AP septum). Our findings provide morphological evidence for interaction of endoderm with SHF and lend support to the hypothesis that the pulmonary endoderm patterns the morphogenesis of cardiac structural components required for establishing efficient systemic and pulmonary circulation.
Part I Coupling of development of pulmonary endoderm with pulmonary endoderm-associated second heart field in mouse embryo
Background and objective:Second heat field (SHF), characterized by islet-1(Isl-1) expression, contribute the cardiac progenitor cells to outflow tract (OFT) and right ventricle for the arterial pole forming after the initial heart tube formation. Conditional deletion of transcription factors or signal proteins from the foregut endoderm result in the malformation of OFT, suggesting that foregut endoderm plays roles in regulation of normal development of OFT and SHF. In order to get insight into the mechanism underlying those OFT malformations, we investigated the morphological relationship of developing trachea groove from foregut endoderm with surrounding Isl-1positive mesenchyme of SHF during OFT development in the normal mouse embryonic heart.
Methods:By immunohistochemistry and double immunofluorescence methods, serial sections of mouse embryos from ED9to ED13were stained with a series of marker antibodies for specifically highlighting SHF (Isl-1), endoderm(Foxa2), basement membrane (Laminin), epithelial polarity (E-cadherin), myocardium (MHC) and smooth muscle (α-SMA) respectively.
Results:At ED9, locally thickened Isl-1positive endoderm in the ventral foregut wall predicted the initiation of pulmonary endoderm differentiation. As soon as the formation of the lanryngo-tracheal groove is initiated at ED9.5, Isl-1positive cells begin to appear in the matrix surrounding the endoderm of the lanryngo-tracheal groove, which we dubbed pulmonary endoderm associated second heart field (PE-Isl-1F). With the elongation of the lanryngo-tracheal groove in the direction of the dorsal wall of the aortic sac from ED10to ED12, the number of Isl-1positive cells in PE-Isl-1F is increased and the distribution of the Isl-1positive cells is closely associated with the pulmonary endoderm in a distinct cone-shaped pattern with its broad base in close apposition to the floor of the foregut and ventral end protruding into the cavity of the aortic sac. During the development of lanryngo-tracheal groove, a solid endoderm cord could always be observed at the ventral end of the lanryngo-tracheal groove from ED10.5to ED12. Pulmonary endoderm of lanryngo-tracheal groove and its solid cord was located in the center of the Isl-1positive PE-Isl-1F. In lanryngo-tracheal groove and PE-Isl-1F development, Laminin positive basement membrane underlying the endoderm appeared as an interrupted or blurred fashion in some regions, accompanied by loss of Foxa2expression and apico-basal polarity in some pulmonary endoderm cells, especially at ED11. At ED13, separation of foregut at the level of outflow tract led to the formation of the trachea, endoderm cord could no longer be found, and expression intensity of Isl-1in PE-Isl-1F was reduced.
Conclusion:The differentiation and development of pulmonary endoderm are closely associated with Isl-1positive mesenchyme aggregation of PE-Isl-1F, and the pulmonary endoderm patterns the PE-Isl-1F formation, between which EMT plays a role.
Part Ⅱ Exclusive expression of SHH receptors in pulmonary endoderm and pulmonary endoderm-associated second heart field
Background and objective:Foregut endoderm has been regarded as one of the sources of SHH ligand and gene ablation or tissue specificity knockout of SHH or Smo in endoderm resulted in various developmental defects of OFT in mouse embryos, but the causes and mechanism of those OFT malformations have not been thoroughly elucidated. It has been demonstrated that the cardiac progenitor cells derived from SHF migrate and form OFT and right ventricle after the primitive cardiac tube formation. In order to demonstrate the morphological relationships of SHH, foregut endoderm and SHF in embryonic heart development, expression patterns of SHH receptors, Ptcl, Ptc2and Smo, were examined in the developing pulmonary endoderm and PE-Isl-1F.
Methods:Serial sections of mouse embryos from ED9to ED13were stained by double immunofluorescence of Ptcl/Isl-1, Ptc2/Isl-1and Smo/Isl-1.
Results:Ptcl and Ptc2began to express exclusively in pulmonary endoderm at ED10. With the ventral growth of pulmonary endoderm to form laryngo-tracheal groove, strong Ptcl and Ptc2expression were mainly confined to the pulmonary endoderm until ED12. Expression of Smo was broad in embryos from ED9to ED13, and mesenchymal cells of PE-Isl-1F surrounding the pulmonary endoderm co-expressed Isl-1and Smo.
Conclusion:SHH signal pathway is involved in the pulmonary endoderm development and the formation of laryngo-tracheal groove and its solid cord by an autocrine or paracrine manner, and also associated with the formation of PE-Isl-1F surrounding the developing pulmonary endoderm.
Part Ⅲ Pulmonary endoderm-associated second heart field and the morphogenesis of the distal outflow tract in mouse embryonic heart
Background and objective:The morphogenesis and septation of the distal outflow tract remains a controversial topic so far. Second heart field (SHF) is reported to contribute the myocardium and the smooth muscle required for OFT development. In this part, the morphological relationship between pulmonary endoderm-associated second heart field (PE-Isl-1F) and the morphogenesis of the intrapericardial trunks during the normal mouse embryos heart development was detected.
Methods:By immunohistochemistry and double immunofluorescence methods, serial sections of mouse embryos from ED9to ED13were stained with a series of marker antibodies for specifically highlighting SHF (Isl-1), myocardium (MHC) and smooth muscle (α-SMA) respectively.
Results:From ED10onward, development of PE-Isl-1F around the laryngo-tracheal groove promoted the continuous extension of its ventral end into the aortic sac to form obvious protrusion. By11.5, though the aortic sac and OFT were still not separated, the extension of PE-Isl-1F to the cranial and caudal myocardial wall of the outflow tract could be detected as Isl-1positive boluses at the level of4th and6th branchial arch arteries, respectively, which are the future lateral walls of intrapericardial aorta and pulmonary trunk. At ED12, expression of Isl-1in protrusion from PE-Isl-1F gradually disappeared and acquired strong a-SMA expression. Then the a-SMA positive protrusion fused with the a-SMA positive distal end of the outflow trunk cushions to form the transient aortic-pulmonary septum (AP septum) and divide aortic sac into the intrapericardial aorta and pulmonary trunks. At ED13, intrapericardial aorta and pulmonary trunk were characterized by disappearance of AP septum and appearance of a-SMA positive smooth muscle layers in their walls.
Conclusion:PE-Isl-1F is involved in patterning the morphogenesis and septation of the intrapericardial arterial trunks.
第一部分呼吸内胚层与呼吸内胚层相关第二生心区的发育耦联
背景与目的：原始心管形成后,被Is1-1标记的第二生心区心前体细胞向流出道和右心室迁移,参与心脏动脉端形成。条件性敲除前肠内胚层的某些相关转录因子或者信号分子导致流出道畸形,提示前肠内胚层在流出道和第二生心区的正常发育调节中扮演重要角色。为了深入了解该类流出道畸形发生的机制,我们观察了正常小鼠胚胎心脏流出道发育过程中,喉-气管沟(前肠内胚层分化而成)与周围第二生心区Is1-1阳性间充质细胞发育的形态学关系。
研究方法：分别用Isl-1标记第二生心区细胞、Foxa2标记内胚层细胞、Laminin标记基膜、E-cadherin标记上皮极性、MHC标记心肌细胞和α-SMA标记平滑肌细胞,对胚胎发育第9-13天鼠胚标本连续切片进行免疫组化染色或者荧光免疫双标染色。
研究结果：胚胎发育第9天,前肠腹侧壁Is1-1阳性的内胚层局部增厚,提示呼吸内胚层分化开始。胚胎发育第9.5天,喉-气管沟发育一经开始,Isl-1阳性细胞就开始出现在喉-气管沟内胚层周围的基质,我们称之为呼吸内胚层相关Is1-1阳性细胞区(PE-Isl-1F)。胚胎发育第10-12天,随着喉-气管沟向动脉囊背侧壁方向生长延伸,PE-Isl-1F的Isl-1阳性细胞的数量增多,Is1-1阳性细胞紧紧围绕呼吸内胚层呈特征性锥体形结构发布,其宽的底边紧贴前肠底壁；腹侧端突入动脉囊腔。喉-气管沟发育过程中,从胚胎发育第10.5天到第12天在喉-气管沟末端总能看到一条实心内胚层细胞索。喉-气管沟及其实心细胞索的呼吸内胚层位于PE-Isl-1F的Isl-1阳性锥体形结构的中心。在喉-气管沟和PE-Isl-1F发育过程中,尤其在胚胎发育第11天,某些部位的内胚层基膜模糊不清或者中断,同时伴有一些呼吸内胚层细胞失去Foxa2表达和上皮极性。胚胎发育第13天,流出道水平的前肠完成分隔、形成气管,内胚层细胞索消失,PE-Isl-1F的Isl-1表达强度减弱。
研究结论：1.呼吸内胚层的分化发育与PE-Isl-1F的Isl-1阳性间充质细胞的发育聚集密切耦联。2.呼吸内胚层诱导PE-Isl-1F形成独特的分布模式。3.上皮-间充质转化与呼吸内胚层和PE-Isl-1F耦联发育有关。
第二部分SHH受体在呼吸内胚层和呼吸内胚层相关第二生心区的独特表达
背景与目的：前肠内胚层是SHH信号分子源之一。基因消融或组织特异性敲除内胚层SHH基因或Smo基因导致多种鼠胚流出道发育畸形,但此类流出道畸形产生的原因和机制并未完全阐明。已知在原始心管形成后,第二生心区的心脏前体细胞通过心背系膜迁移入心脏,参与形成流出道和右心室。为了明确SHH信号通路、前肠内胚层和第二生心区在胚胎心脏发育中的形态学关系,我们观察了SHH受体Ptc1、Ptc2和Smo在呼吸内胚层和PE-Isl-1F发育过程中的表达模式。
研究方法：对胚胎发育第9-13天鼠胚标本连续切片进行Ptc1/Isl-1、Ptc2/Isl-1和Smo/Isl-1的荧光免疫双标染色。
研究结果：胚胎发育第9天,Ptc1和Ptc2开始仅表达于呼吸内胚层。随着呼吸内胚层向腹侧生长形成喉-气管沟,较强的Ptc1和Ptc2主要局限于喉-气管沟的内胚层表达直到胚胎发育第12天。从胚胎发育第9天到第13天,Smo在胚胎各胚层均广泛表达。呼吸内胚层周围的PE-Isl-1F间充质同时表达Isl-1和Smo。
研究结论：1.SHH信号通路以自分泌或旁分泌模式参与呼吸内胚层发育和喉-气管沟及实心细胞索的形成。2.SHH信号通路与呼吸内胚层周围PE-Isl-1F形成有关。
第三部分呼吸内胚层相关第二生心区与小鼠胚胎心脏流出道远端的形态发生
背景与目的：目前流出道远端的形态发生和分隔仍存争议。已知原始心管形成后,第二生心区向流出道添加心肌细胞和平滑肌细胞,参与流出道发育。在该部分,我们观察了小鼠胚胎心脏流出道正常发育过程中,呼吸内胚层相关Isl-1阳性细胞区(PE-Isl-1F)与心包内动脉干形态发生的关系。
研究方法：分别用Isl-1标记第二生心区细胞、MHC标记心肌细胞和α-SMA标记平滑肌细胞,对胚胎发育第9-13天鼠胚标本连续切片进行免疫组化染色或者荧光免疫双标染色。
研究结果：从胚胎发育第10天起,围绕喉-气管沟发育的PE-Isl-1F腹侧末端突入动脉囊,形成明显的“突起”结构。胚胎发育第11.5天,尽管动脉囊和流出道尚未分隔,但分别在第四弓动脉和第六弓动脉水平可见PE-Isl-1F延伸入流出道头端壁和尾端壁,形成流出道远端管壁上的Isl-1阳性细胞团,向未来的心包内主动脉和肺动脉干侧壁分化。胚胎发育第12天,PE-Isl-1F末端“突起”逐渐失去Isl-1表达,获得较强α-SMA表达。尔后α-SMA阳性的PE-Isl-1F“突起”与α-SMA阳性的流出道远端融合,形成暂时性的主-肺动脉隔,将动脉囊分隔为心包内主动脉和肺动脉。胚胎发育第13天,心包内主动脉和肺动脉管壁出现α-SMA阳性平滑肌层,两者间的主-肺动脉隔消失。
研究结论：呼吸内胚层相关第二生心区参与心包内大动脉的形态发生和分隔。
The establishment of efficient systemic and pulmonary circulation relies on the normal morphogenesis and septation of the heart chambers. It has been demonstrated that the cardiac progenitor cells derived from the second heart field (SHF) migrate through dorsal mesocardium to form outflow tract (OFT), right ventricle, part of the atria, and the atrial septum, including the dorsal mesenchymal protrusion, and to populate the aorta and pulmonary trunk. The data from the transgenic mice and gene knockout mouse embryos have revealed that conditional deletion of transcription factors or signal proteins from the foregut endoderm result in the malformation of OFT septation, suggesting that foregut endoderm plays roles in regulation of normal development of OFT and SHF. Major insights on the relationship of foregut endoderm development with the heart development have been gained from the studies of a number of vertebrate and invertebrate models, including mouse, chick, amphibians, et al, via the culture in vitro or the deletion of endoderm genes in vivo. However, in wide-type embryonic mouse, the morphological relationship in the development of foregut endoderm and embryonic heart and the mechanism underlying the interaction between them are seldom described. Sonic hedgehog (SHH) signaling pathway coordinates multiple aspects of cardiovascular growth and development. As a secreted ligand, SHH can only function properly by binding to its receptors, including patchedl (Ptcl), patched2(Ptc2) and smoothened (Smo). Foregut endoderm has been regarded as one of the sources of SHH ligand and conditional abrogation of SHH signaling in foregut endoderm during the cardiac progenitor cell specification leads to the OFT malformation, including persistent truncus arterious, transposition of great arteries, etc. and the atrial and atrioventricular septal defect as well. However, the morphological relationship of expression of SHH signaling pathway members in developing foregut endoderm with development of surrounding SHF and OFT is seldom described. In order to get insight into the mechanism underlying the interaction between foregut endoderm and surrounding Islet-1(Isl-1) positive second heart field mesenchyme, we investigated the morphological relationship of developing trachea groove with SHF during normal OFT development of the mouse embryonic heart, and the expression patterns of Ptc1, Ptc2and Smo, critical receptors in SHH signaling pathway. The results demonstrated that the development of a subset of Isl-1positive field ventral to the foregut is closely coupled with pulmonary endoderm or tracheal groove, and the Isl-1positive cells surrounding the trachea groove is distributed in a special pattern. Because several lines of evidence have demonstrated that the Isl-1positive mesenchyme beneath the foregut floor takes part in the morphogenesis of the heart and therefore is considered to be a subset of the second heart field, we dubbed the subset of Isl-1positive field ventral to the foregut as pulmonary endoderm-associated Isl-1field (PE-Isl-1F). During PE-Isl-1F development, the SHH receptors Ptcl and Ptc2are exclusively expressed in the developing pulmonary endoderm. Close proximity of PE-Isl-1F to the developing trachea groove might be required for and facilitate the specification of the progenitor cells in PE-Isl-1F into cardiac lineage. In addition to taking part in the formation of the lateral walls of the intrapericardial aorta and pulmonary trunk, Isl-1positive cells of PE-Isl-1F surrounding the trachea groove protrude into the aortic sac, together with the distal end of the outflow trunk cushions, to form the transient aortic-pulmonary septum (AP septum). Our findings provide morphological evidence for interaction of endoderm with SHF and lend support to the hypothesis that the pulmonary endoderm patterns the morphogenesis of cardiac structural components required for establishing efficient systemic and pulmonary circulation.
Part I Coupling of development of pulmonary endoderm with pulmonary endoderm-associated second heart field in mouse embryo
Background and objective:Second heat field (SHF), characterized by islet-1(Isl-1) expression, contribute the cardiac progenitor cells to outflow tract (OFT) and right ventricle for the arterial pole forming after the initial heart tube formation. Conditional deletion of transcription factors or signal proteins from the foregut endoderm result in the malformation of OFT, suggesting that foregut endoderm plays roles in regulation of normal development of OFT and SHF. In order to get insight into the mechanism underlying those OFT malformations, we investigated the morphological relationship of developing trachea groove from foregut endoderm with surrounding Isl-1positive mesenchyme of SHF during OFT development in the normal mouse embryonic heart.
Methods:By immunohistochemistry and double immunofluorescence methods, serial sections of mouse embryos from ED9to ED13were stained with a series of marker antibodies for specifically highlighting SHF (Isl-1), endoderm(Foxa2), basement membrane (Laminin), epithelial polarity (E-cadherin), myocardium (MHC) and smooth muscle (α-SMA) respectively.
Results:At ED9, locally thickened Isl-1positive endoderm in the ventral foregut wall predicted the initiation of pulmonary endoderm differentiation. As soon as the formation of the lanryngo-tracheal groove is initiated at ED9.5, Isl-1positive cells begin to appear in the matrix surrounding the endoderm of the lanryngo-tracheal groove, which we dubbed pulmonary endoderm associated second heart field (PE-Isl-1F). With the elongation of the lanryngo-tracheal groove in the direction of the dorsal wall of the aortic sac from ED10to ED12, the number of Isl-1positive cells in PE-Isl-1F is increased and the distribution of the Isl-1positive cells is closely associated with the pulmonary endoderm in a distinct cone-shaped pattern with its broad base in close apposition to the floor of the foregut and ventral end protruding into the cavity of the aortic sac. During the development of lanryngo-tracheal groove, a solid endoderm cord could always be observed at the ventral end of the lanryngo-tracheal groove from ED10.5to ED12. Pulmonary endoderm of lanryngo-tracheal groove and its solid cord was located in the center of the Isl-1positive PE-Isl-1F. In lanryngo-tracheal groove and PE-Isl-1F development, Laminin positive basement membrane underlying the endoderm appeared as an interrupted or blurred fashion in some regions, accompanied by loss of Foxa2expression and apico-basal polarity in some pulmonary endoderm cells, especially at ED11. At ED13, separation of foregut at the level of outflow tract led to the formation of the trachea, endoderm cord could no longer be found, and expression intensity of Isl-1in PE-Isl-1F was reduced.
Conclusion:The differentiation and development of pulmonary endoderm are closely associated with Isl-1positive mesenchyme aggregation of PE-Isl-1F, and the pulmonary endoderm patterns the PE-Isl-1F formation, between which EMT plays a role.
Part Ⅱ Exclusive expression of SHH receptors in pulmonary endoderm and pulmonary endoderm-associated second heart field
Background and objective:Foregut endoderm has been regarded as one of the sources of SHH ligand and gene ablation or tissue specificity knockout of SHH or Smo in endoderm resulted in various developmental defects of OFT in mouse embryos, but the causes and mechanism of those OFT malformations have not been thoroughly elucidated. It has been demonstrated that the cardiac progenitor cells derived from SHF migrate and form OFT and right ventricle after the primitive cardiac tube formation. In order to demonstrate the morphological relationships of SHH, foregut endoderm and SHF in embryonic heart development, expression patterns of SHH receptors, Ptcl, Ptc2and Smo, were examined in the developing pulmonary endoderm and PE-Isl-1F.
Methods:Serial sections of mouse embryos from ED9to ED13were stained by double immunofluorescence of Ptcl/Isl-1, Ptc2/Isl-1and Smo/Isl-1.
Results:Ptcl and Ptc2began to express exclusively in pulmonary endoderm at ED10. With the ventral growth of pulmonary endoderm to form laryngo-tracheal groove, strong Ptcl and Ptc2expression were mainly confined to the pulmonary endoderm until ED12. Expression of Smo was broad in embryos from ED9to ED13, and mesenchymal cells of PE-Isl-1F surrounding the pulmonary endoderm co-expressed Isl-1and Smo.
Conclusion:SHH signal pathway is involved in the pulmonary endoderm development and the formation of laryngo-tracheal groove and its solid cord by an autocrine or paracrine manner, and also associated with the formation of PE-Isl-1F surrounding the developing pulmonary endoderm.
Part Ⅲ Pulmonary endoderm-associated second heart field and the morphogenesis of the distal outflow tract in mouse embryonic heart
Background and objective:The morphogenesis and septation of the distal outflow tract remains a controversial topic so far. Second heart field (SHF) is reported to contribute the myocardium and the smooth muscle required for OFT development. In this part, the morphological relationship between pulmonary endoderm-associated second heart field (PE-Isl-1F) and the morphogenesis of the intrapericardial trunks during the normal mouse embryos heart development was detected.
Methods:By immunohistochemistry and double immunofluorescence methods, serial sections of mouse embryos from ED9to ED13were stained with a series of marker antibodies for specifically highlighting SHF (Isl-1), myocardium (MHC) and smooth muscle (α-SMA) respectively.
Results:From ED10onward, development of PE-Isl-1F around the laryngo-tracheal groove promoted the continuous extension of its ventral end into the aortic sac to form obvious protrusion. By11.5, though the aortic sac and OFT were still not separated, the extension of PE-Isl-1F to the cranial and caudal myocardial wall of the outflow tract could be detected as Isl-1positive boluses at the level of4th and6th branchial arch arteries, respectively, which are the future lateral walls of intrapericardial aorta and pulmonary trunk. At ED12, expression of Isl-1in protrusion from PE-Isl-1F gradually disappeared and acquired strong a-SMA expression. Then the a-SMA positive protrusion fused with the a-SMA positive distal end of the outflow trunk cushions to form the transient aortic-pulmonary septum (AP septum) and divide aortic sac into the intrapericardial aorta and pulmonary trunks. At ED13, intrapericardial aorta and pulmonary trunk were characterized by disappearance of AP septum and appearance of a-SMA positive smooth muscle layers in their walls.
Conclusion:PE-Isl-1F is involved in patterning the morphogenesis and septation of the intrapericardial arterial trunks.
引文
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[1]. Anderson, R.H., B. Chaudhry, T.J. Mohun, S.D. Bamforth, D. Hoyland, H.M. Phillips, S. Webb, A.F. Moorman, N.A. Brown, and D.J. Henderson. Normal and abnormal development of the intrapericardial arterial trunks in humans and mice. Cardiovasc Res,2012,95(1):108-15
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[3]. Kirby, M.L., T.F. Gale, and D.E. Stewart. Neural crest cells contribute to normal aorticopulmonary septation. Science,1983,220(4601):1059-61
[4]. Abu-Issa, R., K. Waldo, and M.L. Kirby. Heart fields:one, two or more? Dev Biol,2004,272(2):281-5
[5]. Cai, C.L., X. Liang, Y. Shi, P.H. Chu, S.L. Pfaff, J. Chen, and S. Evans. Isll identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell,2003, 5(6):877-89
[6]. Sun, Y., X. Liang, N. Najafi, M. Cass, L. Lin, C.L. Cai, J. Chen, and S.M. Evans. Islet 1 is expressed in distinct cardiovascular lineages, including pacemaker and coronary vascular cells. Dev Biol,2007,304(1):286-96
[7]. Hoffmann, A.D., M.A. Peterson, J.M. Friedland-Little, S.A. Anderson, and I.P. Moskowitz. sonic hedgehog is required in pulmonary endoderm for atrial septation. Development,2009,136(10):1761-70
[8]. Yang, Y.P., H.R. Li, X.M. Cao, Q.X. Wang, C.J. Qiao, and J. Ya. Second heart field and the development of the outflow tract in human embryonic heart. Dev Growth Differ,2013,55(3):359-67
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