Department of Chemistry, University of Oxford, Oxford, OX1 3TA, UK.
Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK.
Nat Commun. 2023 Oct 4;14(1):5986. doi: 10.1038/s41467-023-41356-w.
Engineering human tissue with diverse cell types and architectures remains challenging. The cerebral cortex, which has a layered cellular architecture composed of layer-specific neurons organised into vertical columns, delivers higher cognition through intricately wired neural circuits. However, current tissue engineering approaches cannot produce such structures. Here, we use a droplet printing technique to fabricate tissues comprising simplified cerebral cortical columns. Human induced pluripotent stem cells are differentiated into upper- and deep-layer neural progenitors, which are then printed to form cerebral cortical tissues with a two-layer organization. The tissues show layer-specific biomarker expression and develop a structurally integrated network of processes. Implantation of the printed cortical tissues into ex vivo mouse brain explants results in substantial structural implant-host integration across the tissue boundaries as demonstrated by the projection of processes and the migration of neurons, and leads to the appearance of correlated Ca oscillations across the interface. The presented approach might be used for the evaluation of drugs and nutrients that promote tissue integration. Importantly, our methodology offers a technical reservoir for future personalized implantation treatments that use 3D tissues derived from a patient's own induced pluripotent stem cells.
用具有多种细胞类型和结构的工程组织来构建器官仍然具有挑战性。大脑皮层具有分层的细胞结构，由组织成垂直柱的特定于层的神经元组成，通过错综复杂的神经回路实现更高的认知功能。然而，目前的组织工程方法无法产生这种结构。在这里，我们使用液滴打印技术来制造包含简化的大脑皮质柱的组织。人类诱导多能干细胞分化为上和深层神经祖细胞，然后将其打印以形成具有双层组织的大脑皮质组织。这些组织表现出特定于层的生物标志物表达，并形成结构上整合的过程网络。将打印的皮质组织植入体外培养的小鼠脑外植体中，导致组织边界处的结构植入物-宿主整合，这表现为过程的投射和神经元的迁移，并且导致界面处出现相关的 Ca 振荡。所提出的方法可用于评估促进组织整合的药物和营养物质。重要的是，我们的方法为未来使用源自患者自身诱导多能干细胞的 3D 组织的个性化植入治疗提供了技术储备。
