Deciphering immune interactions between human iPSC-derived enteric neural lineages and 3D intestinal epithelial organoids in mucosal inflammation

肠脑轴是一个双向通信系统，由肠神经系统（ENS）等连接。一直以来，炎症性肠病（IBD）可能与神经炎性改变有关，而神经退行性疾病可能与肠道环境的改变有关。ENS调节胃肠道稳态的各个方面，并与肠上皮密切相关。然而，目前尚不清楚这些过程是如何在体内平衡和肠道炎症中被调节的。具体来说，缺乏临床前模型来研究ENS与人类胃肠道（GI）系统复杂环境的相互作用。在这里，我们将利用诱导多能干细胞（iPSC）来源的肠神经系（ENL）结合来自帕金森病（PD）和IBD患者的原代粘膜免疫细胞和上皮细胞，研究ENS与粘膜免疫细胞和上皮细胞之间的免疫串扰。将使用人体器官培养系统和体内人源化小鼠模型对已确定的途径进行功能验证。预期的结果将研究ENL作为神经炎症传感器的作用，并为ENS-GI串扰提供新的见解。这些人体模型可以以自体方式或作为人源化小鼠模型用于个性化医疗的预测系统，并可能导致设计新的治疗干预措施。

The gut-brain axis is a bidirectional communication system, linked by the enteric nervous system (ENS), among others. Consistently, inflammatory bowel diseases (IBD) can be associated with neuroinflammatory changes, while neurodegenerative disorders can be linked to alterations in the intestinal environment. The ENS regulates diverse aspects of gastrointestinal homeostasis and is tightly interrelated with the intestinal epithelium. However, it is unclear how these processes are regulated in the human gut during homeostasis and intestinal inflammation. Specifically, there is a lack of preclinical models to study the interaction of the ENS with the complex environment of the human gastrointestinal (GI) system. Here, we will study immune crosstalk between ENS and mucosal immune and epithelial cells by use of induced pluripotent stem cell (iPSC)-derived enteric neural lineages (ENL) combined with primary mucosal immune and epithelial cells derived from patients with Parkinson disease (PD) and IBD. Functional validation of identified pathways will be performed using human organ culture systems and humanized mouse models in vivo. The expected results will investigate the role of the ENL as a transducer of neuroinflammation and allow new insights into the ENS-GI crosstalk. These human models can be used in an autologous manner or as humanized mouse models for prediction systems in personalized medicine and may lead to the design of novel therapeutic interventions.