Moran Hannah R, Nyarko Obed O, O'Rourke Rebecca, Ching Ryenne-Christine K, Riemslagh Frederike W, Peña Brisa, Burger Alexa, Sucharov Carmen C, Mosimann Christian
Department of Pediatrics, Section of Developmental Biology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
bioRxiv. 2024 Sep 28:2024.09.18.613484. doi: 10.1101/2024.09.18.613484.
The heart integrates diverse cell lineages into a functional unit, including the pericardium, a mesothelial sac that supports heart movement, homeostasis, and immune responses. However, despite its critical roles, the developmental origins of the pericardium remain uncertain due to disparate models. Here, using live imaging, lineage tracking, and single-cell transcriptomics in zebrafish, we find the pericardium forms within the lateral plate mesoderm from dedicated anterior mesothelial progenitors and distinct from the classic heart field. Imaging of transgenic reporters in zebrafish documents lateral plate mesoderm cells that emerge lateral of the classic heart field and among a continuous mesothelial progenitor field. Single-cell transcriptomics and trajectories of -expressing lateral plate mesoderm reveal distinct populations of mesothelial and cardiac precursors, including pericardial precursors that are distinct from the cardiomyocyte lineage. The mesothelial gene expression signature is conserved in mammals and carries over to post-natal development. Light sheet-based live-imaging and machine learning-supported cell tracking documents that during heart tube formation, pericardial precursors that reside at the anterior edge of the heart field migrate anteriorly and medially before fusing, enclosing the embryonic heart to form a single pericardial cavity. Pericardium formation proceeds even upon genetic disruption of heart tube formation, uncoupling the two structures. Canonical Wnt/β-catenin signaling modulates pericardial cell number, resulting in a stretched pericardial epithelium with reduced cell number upon canonical Wnt inhibition. We connect the pathological expression of secreted Wnt antagonists of the SFRP family found in pediatric dilated cardiomyopathy to increased pericardial stiffness: sFRP1 in the presence of increased catecholamines causes cardiomyocyte stiffness in neonatal rats as measured by atomic force microscopy. Altogether, our data integrate pericardium formation as an independent process into heart morphogenesis and connect disrupted pericardial tissue properties such as pericardial stiffness to pediatric cardiomyopathies.
心脏将多种细胞谱系整合为一个功能单元，包括心包，它是一个支持心脏运动、内环境稳态和免疫反应的间皮囊。然而，尽管心包起着关键作用，但由于模型不同，心包的发育起源仍不明确。在这里，我们利用斑马鱼的实时成像、谱系追踪和单细胞转录组学技术，发现心包在侧板中胚层内由专门的前间皮祖细胞形成，且与经典心脏区域不同。斑马鱼转基因报告基因的成像记录了侧板中胚层细胞出现在经典心脏区域的外侧以及连续的间皮祖细胞区域之间。表达的侧板中胚层的单细胞转录组学和轨迹揭示了间皮和心脏前体细胞的不同群体，包括与心肌细胞谱系不同的心包前体细胞。间皮基因表达特征在哺乳动物中是保守的，并延续到出生后的发育阶段。基于光片的实时成像和机器学习支持的细胞追踪记录了在心脏管形成过程中，位于心脏区域前缘的心包前体细胞在融合前向前和向内迁移，包围胚胎心脏形成一个单一的心包腔。即使在心脏管形成的基因破坏情况下，心包形成仍会继续，使这两个结构解耦。经典的Wnt/β-连环蛋白信号调节心包细胞数量，在经典Wnt抑制时导致心包上皮拉伸且细胞数量减少。我们将小儿扩张型心肌病中发现的分泌型Wnt拮抗剂SFRP家族的病理表达与心包僵硬增加联系起来：通过原子力显微镜测量，在儿茶酚胺增加的情况下，sFRP1会导致新生大鼠心肌细胞僵硬。总之，我们的数据将心包形成作为一个独立过程整合到心脏形态发生中，并将心包僵硬等心包组织特性的破坏与小儿心肌病联系起来。
