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Gene therapy of Csf2ra-/- deficiency in long-term cultured fetal monocyte precursors restores bona fide alveolar macrophage development and function in mice

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 cultured with GM-CSF (CSF2-cFLiMo) rapidly differentiate into a long-lived, homogeneous alveolar macrophage (AM)-like population in vitro. CSF2-cFLiMo remained the capacity to develop into bona fide AM 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 AM niches in the lung and protected mice from severe pathology induced by respiratory viral infection, compared to transplantation of macrophages derived from bone marrow 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 FLiMo and demonstrated 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 dissect AM development and function and pulmonary transplantation therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE193537 | GEO | 2022/01/15

REPOSITORIES: GEO

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