Bona fide alveolar macrophage generation from long-term in vitro culture of fetal precursors provides a novel platform for gene therapy and functional studies

Li, F.; Okreglicka, K. M.; Pohlmeier, L. M.; Schneider, C.; Kopf, M.

doi:10.1101/2021.06.04.447115

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bioRxiv · 10.1101/2021.06.04.447115

Bona fide alveolar macrophage generation from long-term in vitro culture of fetal precursors provides a novel platform for gene therapy and functional studies

Li, F.·Okreglicka, K. M.·Pohlmeier, L. M.·Schneider, C.·Kopf, M.

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Abstract

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 show that fetal liver monocytes (FLiMo) cultured with GM-CSF (also known as CSF2) rapidly differentiate into a long-lived, homogeneous alveolar macrophage (AM)-like population in vitro. CSF2-cultured FLiMo remain the capacity to develop into bona fide AM upon transfer into Csf2ra-/- neonates and prevent development of alveolar proteinosis and efferocytosis of apoptotic cells for at least 1 year in vivo. Compared to transplantation of AM-like cells derived from bone marrow macrophages (BMM), CSF2-cFliMo more efficiently engraft empty AM niches in the lung and protect mice from respiratory viral infection. Harnessing the potential of this approach for gene therapy, we restored a disrupted Csf2ra gene in FLiMo and their capacity to develop into AM in vivo. Together, we provide a novel platform for generation of immature AM-like precursors amenable for genetic manipulation, which will be useful to study to dissect AM development and function and pulmonary transplantation therapy.

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Li, F., Okreglicka, K. M., Pohlmeier, L. M., Schneider, C., Kopf, M.. 2021-06-05. Bona fide alveolar macrophage generation from long-term in vitro culture of fetal precursors provides a novel platform for gene therapy and functional studies. https://doi.org/10.1101/2021.06.04.447115

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