Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Tissue-resident macrophage

• Alveolar macrophage

• Myeloid cells

Main Findings

• 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).

Limitations

• 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.

Significance/Novelty

• 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.

Credit

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.