Malheiro Afonso, Harichandan Abhishek, Bernardi Joyce, Seijas-Gamardo Adrián, Konings Gonda F, Volders Paul G A, Romano Andrea, Mota Carlos, Wieringa Paul, Moroni Lorenzo
MERLN Institute for Technology-Inspired Regenerative Medicine, Complex Tissue Regeneration department, Maastricht University, Maastricht, The Netherlands.
CARIM School for Cardiovascular Diseases, Department of Cardiology, Maastricht University, Maastricht, The Netherlands.
Biofabrication. 2021 Nov 30;14(1). doi: 10.1088/1758-5090/ac36bf.
Functional humanizednerve models are coveted as an alternative to animal models due to their ease of access, lower cost, clinical relevance and no need for recurrent animal sacrifice. To this end, we developed a sensory nerve model using induced pluripotent stem cells-derived nociceptors that are electrically active and exhibit a functional response to noxious stimuli. The differentiated neurons were co-cultured with primary Schwann cells on an aligned microfibrous scaffold to produce biomimetic peripheral nerve tissue. Compared to glass coverslips, our scaffold enhances tissue development and stabilization. Using this model, we demonstrate that myelin damage can be induced from hyperglycemia exposure (glucose at 45 mM) and mitigated by epalrestat (1M) supplementation. Through fibrin embedding of the platform, we were able to create 3D anisotropic myelinated tissue, reaching over 6.5 mm in length. Finally, as a proof-of-concept, we incorporated pancreatic pseudoislets and endometrial organoids into our nerve platform, to demonstrate the potential in generating nociceptor innervation models. In summary, we propose here an improved tool for neurobiology research with potential applications in pathology modeling, drug screening and target tissue innervation.
功能性人源化神经模型因其易于获取、成本较低、临床相关性强且无需反复牺牲动物而备受青睐，有望成为动物模型的替代方案。为此，我们利用诱导多能干细胞来源的伤害感受器开发了一种感觉神经模型，这些伤害感受器具有电活性，并对有害刺激表现出功能性反应。将分化的神经元与原代雪旺细胞在排列好的微纤维支架上共培养，以生成仿生外周神经组织。与玻璃盖玻片相比，我们的支架可促进组织发育并增强稳定性。利用该模型，我们证明高血糖暴露（45 mM葡萄糖）可诱导髓鞘损伤，而补充依帕司他（1M）可减轻这种损伤。通过将平台纤维蛋白包埋，我们能够创建3D各向异性有髓组织，长度超过6.5毫米。最后，作为概念验证，我们将胰腺假胰岛和子宫内膜类器官纳入我们的神经平台，以证明生成伤害感受器神经支配模型的潜力。总之，我们在此提出一种改进的神经生物学研究工具，在病理建模、药物筛选和靶组织神经支配方面具有潜在应用价值。
