Department of Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany.
Department of Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, Connecticut 06877, United States.
SLAS Discov. 2024 Oct;29(7):100185. doi: 10.1016/j.slasd.2024.100185. Epub 2024 Sep 26.
Human induced pluripotent stem cell (iPSC)-derived macrophages (IDMs) present a valuable substitute for monocyte-derived macrophages (MDMs) in order to study inflammation pathways in vitro. Through optimization of an IDM differentiation protocol, a six-fold increase in the production yield of myeloid progenitors was achieved. The derived IDMs were further characterized with respect to nucleotide-binding oligomerization domain (NOD) and receptor-interacting serine/threonine-protein kinase 2 (RIPK2) signaling, a key regulatory pathway for autoimmune diseases. The IDM cells recapitulated MDM biology with respect to the proinflammatory chemokine and inflammatory cytokine fingerprint more closely than THP-1 cells. When assessing RIPK2 modulation effect on tumor necrosis factor α (TNF-α), a cardinal mediator of inflammation, a similar pharmacological effect of RIPK2 inhibitors was observed in IDMs and MDMs. Additionally, IDMs and MDMs displayed a similar transcription and pathway profile in response to NOD1/2 stimulation and pharmacological inhibition of RIPK2. In summary, the enhanced myeloid production yield in the improved IDM differentiation protocol offers new opportunities for utilizing physiologically relevant macrophage models in the context of inflammatory diseases.
人诱导多能干细胞（iPSC）衍生的巨噬细胞（IDM）为研究体外炎症通路提供了一种有价值的单核细胞衍生巨噬细胞（MDM）替代物。通过优化 IDM 分化方案，骨髓祖细胞的产量增加了六倍。进一步对衍生的 IDM 进行核苷酸结合寡聚化结构域（NOD）和受体相互作用丝氨酸/苏氨酸蛋白激酶 2（RIPK2）信号转导的特征分析，该信号通路是自身免疫性疾病的关键调控途径。IDM 细胞在促炎趋化因子和炎症细胞因子特征指纹方面比 THP-1 细胞更接近地再现了 MDM 生物学。在评估 RIPK2 对肿瘤坏死因子 α（TNF-α）的调节作用时，在 IDM 和 MDM 中观察到 RIPK2 抑制剂的类似药理学效应，TNF-α是炎症的主要介质。此外，IDM 和 MDM 对 NOD1/2 刺激和 RIPK2 的药理学抑制的反应表现出相似的转录和途径特征。总之，在改进的 IDM 分化方案中增加的骨髓祖细胞产量为在炎症性疾病背景下利用生理相关的巨噬细胞模型提供了新的机会。
