A cross-institutional Journal Club Initiative
Murine ex vivo cultured alveolar macrophages provide a novel tool to study tissue-resident macrophage behavior and function
Gorki A.-D. et al. (BioRxiv) DOI: 10.1101/2021.02.11.430791
The ex vivo study of specialized tissue-resident myeloid cells, such as alveolar macrophages (AM), has been limited by lack of reliable models and the absence of consistent tissue cues.
This study proposes a novel culture model to differentiate fetal-liver monocytes or expand murine primary AMs over several months by providing a combination of GM-CSF, TGFβ and the PPARγ agonist rosiglitazone. Termed mexAMs, these ex-vivo AMs recapitulate typical morphologic features and express primary AM surface markers throughout in vitro culture.
mexAMs respond to microbial ligands and exhibit an AM-like lineage transcriptional profile, but are metabolically more active and cycling differently than primary AMs.
Importantly, mexAMs efficiently engraft in the lung when transferred into AM-deficient mice and carry out AM functions, as shown by a reduction in surfactant load in such a model of alveolar proteinosis (PAP).
The study would benefit from digging deeper into transcriptional differences observed between mexAMs and primary AMs, especially in metabolic pathways.
It would be important to compare the plasticity and fidelity of mexAMs to fetal-liver-derived AMs (same study) and iPSC-derived iAMs (Takata Immunity 2017)
The observation that primary AMs outcompete mexAMs in a competitive transfer model indicates a ‘fitness’ issue for long-term engraftment of mexAMs, which isn’t followed up on.
Going beyond PAP, the authors could utilize other models of infection (RSV, Mtb, SARS-CoV2) to demonstrate AM-like functional abilities.
Demonstrating that a similar strategy works with human AMs extracted from PAP patient lavage would enhance the translational impact and significance; currently the study uses only mouse cells.
The study is a clear advance in culturing and expanding AMs over several months ex vivo, using rational growth factors and lineage-determining transcription factor agonist. This has clear significance both in terms of basic immunology studies (that require ex vivo models for tissue-resident AMs) and translational/clinical studies (manipulating or influencing AM phenotype).
As mexAMs proliferate and metabolize distinctly from primary AMs; studies can exploit this for modeling niche-replacement (e.g.- proliferative response to injury or AM infection)
Overall, this report also provides a proof-of-concept to generate other tissue-resident myeloid programs using educated design of survival+tissue cues. This can be very powerful platform to bio-engineer tissue-resident myeloid cells and reintroduce into patients with restored/modified function.
Reviewed by Samarth Hegde as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow him on Twitter.