Axonal Length Determines Distinct Homeostatic Phenotypes in Human iPSC Derived Motor Neurons on a Bioengineered Platform.
Axonal Length Determines Distinct Homeostatic Phenotypes in Human iPSC Derived Motor Neurons on a Bioengineered Platform.
复制标题
轴突长度决定生物工程平台上人类 iPSC 衍生的运动神经元的独特稳态表型。
DOI：
10.1002/adhm.202101817
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发表时间：
2022
影响因子：
10
通讯作者：
Hagemann C
中科院分区：
文献类型：
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作者：
Hagemann C
基于干细胞的神经科学实验平台可以有效地模拟人类发育和疾病的关键机制方面。然而，传统的培养系统常常忽视细胞在体内面临的工程限制。这对于覆盖长距离连接的神经元（例如脊髓运动神经元（MN））特别相关。它们的轴突长达1米，需要复杂的相互作用机制来维持细胞内稳态。然而，传统文化中较短的轴突可能无法忠实地捕捉其较长对应物的重要方面。在这里，这个问题直接通过建立一个生物工程平台来组装从微米到厘米的人类轴突阵列来解决，这首次允许系统地研究长度对人类轴突的影响。这种方法揭示了体外人MN的长度和代谢之间的联系，其中轴突超过“阈值”大小诱导细胞骨架组成，功能特性，局部翻译和线粒体稳态的特定分子适应。这些发现特别证明了存在一种长度依赖性机制，该机制在人类MN内切换稳态过程。这些发现对几种神经退行性疾病的体外建模具有重要意义，并加强了体外逼真和精确建模细胞形状和生物物理约束的重要性。
Stem cell‐based experimental platforms for neuroscience can effectively model key mechanistic aspects of human development and disease. However, conventional culture systems often overlook the engineering constraints that cells face in vivo. This is particularly relevant for neurons covering long range connections such as spinal motor neurons (MNs). Their axons extend up to 1m in length and require a complex interplay of mechanisms to maintain cellular homeostasis. However, shorter axons in conventional cultures may not faithfully capture important aspects of their longer counterparts. Here this issue is directly addressed by establishing a bioengineered platform to assemble arrays of human axons ranging from micrometers to centimeters, which allows systematic investigation of the effects of length on human axonas for the first time. This approach reveales a link between length and metabolism in human MNs in vitro, where axons above a “threshold” size induce specific molecular adaptations in cytoskeleton composition, functional properties, local translation, and mitochondrial homeostasis. The findings specifically demonstrate the existence of a length‐dependent mechanism that switches homeostatic processes within human MNs. The findings have critical implications for in vitro modeling of several neurodegenerative disorders and reinforce the importance of modeling cell shape and biophysical constraints with fidelity and precision in vitro.