荷兰阿姆斯特丹大学Harsha D. Devalla研究组使用源自人类多能干细胞的心脏组装体模拟房室传导轴。相关论文于2024年9月10日在线发表在《细胞—干细胞》杂志上。

研究人员表示，房室（AV）传导轴为心房和心室之间提供电信号的连续性。分布在这一区域的“结”型心肌细胞（胚胎中的AV管，胎儿期开始为AV结）缓慢传播搏动，确保心房和心室的顺序收缩。AV结组织功能障碍会导致严重的节律和收缩紊乱，目前捕捉其主要特征的人类模型较为有限。

研究人员提出了一种可重复生成具有体内样基因表达和电生理特征的AV管心肌细胞（AVCM）的方法。研究人员构建了由心房、AVCM和心室类球组成的“组装体”，有效再现了脊椎动物心脏典型的单向传导和“快-慢-快”激活模式。

研究人员利用这些系统揭示了LMNA相关的AV传导阻滞的基础是细胞内钙处理异常。总之，该研究引入了新的细胞分化和组织构建策略，以促进对影响心脏节律的复杂疾病的研究。

附：英文原文

Title: Modeling the atrioventricular conduction axis using human pluripotent stem cell-derived cardiac assembloids

Author: Jiuru Li, Alexandra Wiesinger, Lianne Fokkert, Priscilla Bakker, Dylan K. de Vries, Anke J. Tijsen, Yigal M. Pinto, Arie O. Verkerk, Vincent M. Christoffels, Gerard J.J. Boink, Harsha D. Devalla

Issue&Volume: 2024-09-10

Abstract: The atrioventricular (AV) conduction axis provides electrical continuity between the atrial and ventricular chambers. The “nodal” cardiomyocytes populating this region (AV canal in the embryo, AV node from fetal stages onward) propagate impulses slowly, ensuring sequential contraction of the chambers. Dysfunction of AV nodal tissue causes severe disturbances in rhythm and contraction, and human models that capture its salient features are limited. Here, we report an approach for the reproducible generation of AV canal cardiomyocytes (AVCMs) with in vivo-like gene expression and electrophysiological profiles. We created the so-called “assembloids” composed of atrial, AVCM, and ventricular spheroids, which effectively recapitulated unidirectional conduction and the “fast-slow-fast” activation pattern typical for the vertebrate heart. We utilized these systems to reveal intracellular calcium mishandling as the basis of LMNA-associated AV conduction block. In sum, our study introduces novel cell differentiation and tissue construction strategies to facilitate the study of complex disorders affecting heart rhythm.

DOI: 10.1016/j.stem.2024.08.008

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00294-7