Rezvani Milad
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Berlin, Germany.
Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany.
Cell Mol Immunol. 2025 Jul 2. doi: 10.1038/s41423-025-01312-8.
The liver hosts a variety of immune cells while creating a tolerogenic environment under homeostatic conditions. However, most chronic liver diseases shift toward inflammation over time. Understanding and intercepting the crosstalk between various immune cells and liver tissue is crucial, as it is often the rate-limiting factor in preclinical drug development. Owing to significant interspecies differences in liver immunology, human models, such as classical cocultures or organogenesis-inspired liver organoids with immune compartments, are becoming essential for advancing the field. Therefore, this review evaluates human-specific models of hepatic-immune crosstalk and assesses a range of models from basic 2D cultures to microphysiological systems (MPSs) and advanced multitissue organoids. It serves as a guide for experimentalists to identify suitable approaches. For example, traditional cocultures offer robustness, reductionist approaches, and modularity but have limited spatial fidelity and cell heterogeneity. In contrast, multitissue organoids inspired by mammalian ontogeny are created from pluripotent stem cells and integrate multiple tissue niche-constituting cells, which include Kupffer-like cells. In conclusion, this review discusses progress in human liver immunology modeling and highlights limitations and numerous untapped opportunities. These include the potential to model in vitro autoimmunity and more complex myeloid inflammatory responses, incorporating contributions from embryonic tissue and bone marrow. Additionally, future in vitro models may include hard-to-culture populations such as neutrophils.
肝脏在稳态条件下容纳多种免疫细胞，同时营造出一种免疫耐受环境。然而，大多数慢性肝病会随着时间的推移而转向炎症状态。理解并阻断各种免疫细胞与肝组织之间的相互作用至关重要，因为这往往是临床前药物研发中的限速因素。由于肝脏免疫学存在显著的种间差异，人类模型，如经典共培养或带有免疫区室的受器官发生启发的肝脏类器官，对于推动该领域的发展正变得至关重要。因此，本综述评估了肝脏 - 免疫相互作用的人类特异性模型，并评估了一系列从基础二维培养到微生理系统（MPS）以及先进的多组织类器官的模型。它为实验人员识别合适的方法提供了指导。例如，传统共培养具有稳健性、还原论方法和模块化，但空间保真度和细胞异质性有限。相比之下，受哺乳动物个体发育启发的多组织类器官由多能干细胞生成，并整合了多种构成组织生态位的细胞，其中包括类库普弗细胞。总之，本综述讨论了人类肝脏免疫学建模的进展，并强调了局限性和众多未开发的机会。这些机会包括在体外模拟自身免疫和更复杂的髓系炎症反应的潜力，纳入胚胎组织和骨髓的贡献。此外，未来的体外模型可能包括难以培养的细胞群体，如中性粒细胞。
