hiPSC-derived macrophages improve drug sensitivity and selectivity in a macrophage-incorporating organoid culture model

초록

Accurate simulation of different cell type interactions is crucial for physiological and precise in vitro drug 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 in in vitro modeling. 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 sensitive in vitro drug evaluation and screening systems. © 2024 The Author(s). Published by IOP Publishing Ltd.

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