Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea.
Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
Biofabrication. 2024 May 28;16(3). doi: 10.1088/1758-5090/ad4c0a.
Accurate simulation of different cell type interactions is crucial for physiological and precisedrug testing. Human tissue-resident macrophages are critical for modulating disease conditions and drug-induced injuries in various tissues; however, their limited availability has hindered their use inmodeling. Therefore, this study aimed to create macrophage-containing organoid co-culture models by directly incorporating human-induced pluripotent stem cell (hiPSC)-derived pre-macrophages into organoid and scaffold cell models. The fully differentiated cells in these organoids exhibited functional characteristics of tissue-resident macrophages with enriched pan-macrophage markers and the potential for M1/M2 subtype specialization upon cytokine stimulation. In a hepatic organoid model, the integrated macrophages replicated typical intrinsic properties, including cytokine release, polarization, and phagocytosis, and the co-culture model was more responsive to drug-induced liver injury than a macrophage-free model. Furthermore, alveolar organoid models containing these hiPSC-derived macrophages also showed increased drug and chemical sensitivity to pulmonary toxicants. Moreover, 3D adipocyte scaffold models incorporating macrophages effectively simulated in vivo insulin resistance observed in adipose tissue and showed improved insulin sensitivity on exposure to anti-diabetic drugs. Overall, the findings demonstrated that incorporating hiPSC-derived macrophages into organoid culture models resulted in more physiological and sensitivedrug evaluation and screening systems.
准确模拟不同类型的细胞相互作用对于生理和精确的药物测试至关重要。人类组织驻留巨噬细胞对于调节各种组织中的疾病状况和药物引起的损伤至关重要；然而，它们的有限可用性阻碍了它们在建模中的应用。因此，本研究旨在通过直接将人诱导多能干细胞（hiPSC）衍生的前巨噬细胞纳入类器官和支架细胞模型来创建含有巨噬细胞的类器官共培养模型。这些类器官中的完全分化细胞表现出组织驻留巨噬细胞的功能特征，具有丰富的泛巨噬细胞标志物，并在细胞因子刺激下具有 M1/M2 亚型特化的潜力。在肝类器官模型中，整合的巨噬细胞复制了典型的内在特性，包括细胞因子释放、极化和吞噬作用，并且与无巨噬细胞模型相比，共培养模型对药物诱导的肝损伤更敏感。此外，含有这些 hiPSC 衍生巨噬细胞的肺泡类器官模型也显示出对肺毒物的药物和化学敏感性增加。此外，将巨噬细胞纳入 3D 脂肪细胞支架模型可有效模拟体内脂肪组织中观察到的胰岛素抵抗，并在接触抗糖尿病药物时显示出改善的胰岛素敏感性。总体而言，这些发现表明将 hiPSC 衍生的巨噬细胞纳入类器官培养模型可产生更生理和敏感的药物评估和筛选系统。
