Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
Institute of Physiology, University of Zurich, Zurich, Switzerland.
JCI Insight. 2022 Apr 8;7(7):e152271. doi: 10.1172/jci.insight.152271.
Tissue-resident macrophage-based immune therapies have been proposed for various diseases. However, generation of sufficient numbers that possess tissue-specific functions remains a major handicap. Here, we showed that fetal liver monocytes cultured with GM-CSF (CSF2-cFLiMo) rapidly differentiated into a long-lived, homogeneous alveolar macrophage-like population in vitro. CSF2-cFLiMo retained the capacity to develop into bona fide alveolar macrophages upon transfer into Csf2ra-/- neonates and prevented development of alveolar proteinosis and accumulation of apoptotic cells for at least 1 year in vivo. CSF2-cFLiMo more efficiently engrafted empty alveolar macrophage niches in the lung and protected mice from severe pathology induced by respiratory viral infection compared with transplantation of macrophages derived from BM cells cultured with M-CSF (CSF1-cBMM) in the presence or absence of GM-CSF. Harnessing the potential of this approach for gene therapy, we restored a disrupted Csf2ra gene in fetal liver monocytes and demonstrated their capacity to develop into alveolar macrophages in vivo. Altogether, we provide a platform for generation of immature alveolar macrophage-like precursors amenable for genetic manipulation, which will be useful to dissect alveolar macrophage development and function and for pulmonary transplantation therapy.
基于组织驻留巨噬细胞的免疫疗法已被提议用于各种疾病。然而，产生具有组织特异性功能的足够数量的细胞仍然是一个主要障碍。在这里，我们表明，用 GM-CSF（CSF2-cFLiMo）培养的胎肝单核细胞在体外迅速分化为具有长寿命、均质的肺泡巨噬细胞样群体。CSF2-cFLiMo 保留了在 Csf2ra-/- 新生儿体内发育为真正的肺泡巨噬细胞的能力，并在体内至少 1 年内防止了肺泡蛋白沉积症的发展和凋亡细胞的积累。CSF2-cFLiMo 比在 GM-CSF 存在或不存在的情况下用 M-CSF（CSF1-cBMM）培养的 BM 细胞衍生的巨噬细胞移植更有效地植入空的肺泡巨噬细胞龛位，并保护小鼠免受呼吸病毒感染引起的严重病理损伤。利用这种方法的潜力进行基因治疗，我们恢复了胎肝单核细胞中破坏的 Csf2ra 基因，并证明了它们在体内发育为肺泡巨噬细胞的能力。总的来说，我们提供了一个生成易于遗传操作的未成熟肺泡巨噬细胞样前体的平台，这将有助于剖析肺泡巨噬细胞的发育和功能，并用于肺移植治疗。
