Hematopoietic stem cell requirement for macrophage regeneration is tissue-specific

Eddins, D.J. et al. (BioRxiv) DOI: 10.1101/2021.04.08.439077



  • Peritoneal macrophages

  • Ontogeny

  • Tissue-resident macrophages


Main Findings

  • In this preprint, Eddins et al. described that first myeloid cells appear in the peritoneum and the brain before the development of long-term haematopoietic stem cells (LT-HSCs) suggesting that both peritoneal macrophages and microglia are yolk sac-derived. By labelling yolk sac progenitors, they were able to show that at least a fraction of both tissue-resident peritoneal macrophages and microglia are indeed derived from yolk sac progenitors. Furthermore, they showed that both fetal liver and adult bone marrow LT-HSC are able to regenerate peritoneal macrophages, however, microglia cannot be regenerated in the same way. Finally, they showed that yolk sac-derived and LT-HSC-derived peritoneal macrophages are functionally similar, specifically express similar transcription factors and are able to phagocytose bacteria to the similar extent.


  • The assessment of functional similarity between yolk sac-derived and LT-HSC-derived peritoneal macrophages was rather superficial. Investigating the morphology, specific localisation within the peritoneal cavity, interactions within their niches, their behaviour in inflammatory conditions (e.g. peritonitis) and other assessments would add to the notion that yolk sac-derived and LT-HSC-derived macrophages are functionally the same.

  • Potentially comparing the ontogeny and regeneration of peritoneal macrophages to a different population of macrophages residing also in a cavity might be more informative than a comparison to microglia. The damage and therefore a need for faster regeneration would be most likely greater in cavities than in the central nervous system.

  • The fact that only a small fraction of cells in both the brain and peritoneal cavity were labelled in the Runx1-eGFP tracing experiment could be addressed in the paper (e.g. if it is caused by efficacy of the labelling, detection problems, using a different marker as a driver etc.).

  • The methods mention that total of 40 mice received LT-HSC transplantation (13 adult BM, 27 fetal liver), of those 26 became chimeric (11 BM, 15 fetal liver) and authors selected cohort with the highest chimerism (n=15; 4 adult BM, 11 fetal liver). I understand the need to select chimeric mice for the downstream experiments, however, pre-selection of a cohort might skew the data reported.


  • This preprint addressed the discrepancies in the literature regarding the ontogeny of peritoneal macrophages. Previously, it was shown that macrophages in the peritoneal cavity are regenerated with both minimal and substantial contribution from circulating monocytes (Yona et al. 2013, Hashimoto et al. 2013, Sheng et al. 2015; Epelman et al. 2014). The dual ontogeny presented in this work potentially explains these previous contradictory observations.

  • The presence and/or proper function of tissue-resident macrophages often correlate with resolution of chronic inflammatory diseases. Moreover, tissue-resident macrophages were shown to protect against excessive neutrophil recruitment by cloaking the tissue damage and therefore preventing excessive inflammation (Uderhardt et al. 2019). Better understanding of the repopulation of these macrophages could potentially lead to drugs that could expedite their regeneration and thus trigger their protective function in inflammatory conditions.

  • Additionally, this preprint emphasised that we cannot draw parallels between ontogenies of different tissue-resident macrophages as those appear to be tissue-specific.


Reviewed by Barbora Schonfeldova 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 her on Twitter