Alveolar macrophages (AMs) are lung tissue-resident macrophages that can be expanded in culture, but it is unknown to what extent culture affects their in vivo identity.
T cells can be generated in large numbers for cancer cellular therapies, the proliferative capacity of macrophages in culture is very limited16,17. All common macrophage culture protocols therefore have the drawback to only generate a limited number of cells that are heterogenous and usable only in the short term.
Mouse AMs constitutively express low levels of the antiproliferative transcription factors MafB and cMaf, which enables them to access a network of self-renewal genes that are repressed by these Maf factors in other macrophage populations18,19. As a consequence, AMs can expand in culture to large numbers and proliferate for extended periods of time19,20. It is therefore of high interest for experimental science and potential cellular therapy applications in cancer immunology, infectious disease and regenerative medicine as to whether macrophage identity can be maintained through long-term proliferation in culture.
Scientists from Germany have compared the transcriptional and epigenetic identity of mouse AMs in long-term culture before and after re-transplantation into the lung niche environment. We observed that the substantial adaptations of AMs to the culture environment were transient and did not compromise the functional long-term integration into the lung alveolar niche. After transplantation, ex vivo exAMs had a transcriptional and epigenetic signature that was almost indistinguishable from resident AMs that had never transitioned through culture, even after long-term proliferation in culture. This indicated that AMs sustained sensitivity to critical in vivo environmental cues through long periods of culture and represent a unique high-fidelity culture that can shuttle between ex vivo experimental manipulation and in vivo validation. Our observations also suggest that macrophage expansion ex vivo can provide large-scale preparations for cellular therapy applications with maintained healthy macrophage identity in vivo.
Here they show that mouse long-term ex vivo expanded AMs (exAMs) maintained a core AM gene expression program, but showed culture adaptations related to adhesion, metabolism and proliferation. Upon transplantation into the lung, exAMs reacquired full transcriptional and epigenetic AM identity, even after several months in culture and could self-maintain long-term in the alveolar niche. Changes in open chromatin regions observed in culture were fully reversible in transplanted exAMs and resulted in a gene expression profile indistinguishable from resident AMs. Their results indicate that long-term proliferation of AMs in culture did not compromise cellular identity in vivo. The robustness of exAM identity provides new opportunities for mechanistic analysis and highlights the therapeutic potential of exAMs.
Sherry
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