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Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart

Thomas J. Cahill, Xin Sun, Christophe Ravaud, Cristina Villa del Campo, Konstantinos Klaourakis, Irina-Elena Lupu, Allegra M. Lord, Cathy Browne, Sten Eirik W. Jacobsen, David R. Greaves, David G. Jackson, Sally A. Cowley, William James, Robin P. Choudhury, Joaquim Miguel Vieira, Paul R. Riley

Posted on: 25 August 2020

Preprint posted on 2 July 2020

Article now published in Development at http://dx.doi.org/10.1242/dev.194563

Macrophages regulate lymphatic vessel growth during development

Selected by Jonny Coates

Background

Macrophages are multifunctional innate immune cells that have key roles in immune responses, healing, development and homeostasis (1). During development, macrophages seed different tissues where the local microenvironment imprints a specific genetic signature, creating specialised tissue resident macrophages (2). The tissue resident macrophages are then essential for development of their associated tissue. During embryogenesis, this process occurs when macrophages become resident within the developing heart (3).

The heart is a highly vascularised organ with lymphatic capillaries and collecting lymphatic vessels making up the cardiac lymphatic vasculature (4). Recently, it has emerged that the lymphatic vasculature may represent an important therapeutic target, particularly in relation to lymphoangiogensis (5). Therefore, understanding how the cardiac lymphatics develop is an important step towards this.

Cahill et al investigated the importance and role of cardiac macrophages for lymphatic vessel growth within the developing heart.

 

Key findings

  1. Macrophages are associated with developing lymphatics

As heart development progresses, the number of macrophages present increase. Therefore, the authors imaged mid-stage mouse embryos (E12.5-E16.5) to investigate the localisation of macrophages with developing lymphatics. They found that macrophages are localised with the developing lymphatics and that removal of macrophages in mutants which lacked myeloid cells lymphatic development was stunted, with reduced length and numbers of junctions (figure 1).

Tissue resident macrophages can either be recruited from circulating monocytes or seeded by yolk-sac derived macrophages and self-renew. To address this, the authors stained with markers of these different ontogenies and found that the yolk-sac derived macrophages were those associated with developing lymphatics. The loss of these macrophages subsequently impaired lymphatic growth, though to a lesser degree than when all myeloid cells were removed.

  1. Hyaluronan is essential for promoting lymphatic cell network formation and sprouting

Hyaluronan is a key component of the extracellular matrix which has roles in regulating inflammation, including through the recruitment of immune cells (6). The authors treated macrophages with Hyaluronidase (an enzyme that breaks down hyaluronan) and found that this reduced lymphatic sprouting.

This finding is important as it suggests that the macrophages are forming direct cell-cell contacts with the endothelial cells, providing a potential mechanism of action in the developing heart lymphatics. There are a number of hyaluronan binding proteins (7) which leaves scope for future investigations into the exact mechanism at play.

 

Why I chose this preprint

I have a deep affection for macrophages and imaging. This work further shows just how incredible macrophages are at multitasking and is an excellent use of microscopy to reveal concepts that would be difficult to otherwise understand and observe – And of course, the images are beautiful.

 

Open questions

 

  1. What do the authors believe the macrophages are doing at the lymphatic branch points? Are the macrophages phagocytosing material or secreting specific cytokines or growth factors? Do the authors have further evidence that the macrophage activities dependent on cell-cell interactions as they suggest?
  2. If direct macrophage-endothelial cell contacts are required, how do the author propose these are mediated? Could specific genes be knocked-out to prevent this direct contact, for example E-cadherin?

 

References

  1. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013 Apr 25;496(7446):445–55.
  2. A-Gonzalez N, Quintana JA, García-Silva S, Mazariegos M, Aleja AG de la, Nicolás-Ávila JA, et al. Phagocytosis imprints heterogeneity in tissue-resident macrophages. J Exp Med. 2017 Apr 20;jem.20161375.
  3. Ma Y, Mouton AJ, Lindsey ML. Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction. Transl Res J Lab Clin Med. 2018 Jan;191:15–28.
  4. Huang L-H, Lavine KJ, Randolph GJ. Cardiac Lymphatic Vessels, Transport, and Healing of the Infarcted Heart. JACC Basic Transl Sci. 2017 Aug 28;2(4):477–83.
  5. Liu X, Oliver G. New insights about the lymphatic vasculature in cardiovascular diseases. F1000Research [Internet]. 2019 Oct 29 [cited 2020 Aug 13];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820817/
  6. Petrey AC, de la Motte CA. Hyaluronan, a Crucial Regulator of Inflammation. Front Immunol [Internet]. 2014 [cited 2020 Aug 13];5. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2014.00101/full
  7. Day AJ, Prestwich GD. Hyaluronan-binding Proteins: Tying Up the Giant. J Biol Chem. 2002 Feb 15;277(7):4585–8.

Tags: heart development, immunology, macrophage, microscopy

doi: https://doi.org/10.1242/prelights.17797

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