Key result
Loss of adma cuts cardiac lymphatic sprouts up to ~80% and impairs neutrophil clearance.
Why the study?
The mechanisms underlying cardiac lymphatic vessel formation and function during heart development and regeneration remain unclear.
Adma and its decoy receptor Ackr3a play opposing, critical roles in regulating cardiac lymphatic vessel formation, lymphatic endothelial cell heterogeneity, and immune cell clearance during heart regeneration.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Compared with cardiac muscle cells and blood vessels, we know relatively little about the heart's lymphatic vessels. Learning how these vessels develop is an important first step in uncovering what happens when they do not function properly.”
Zebrafish adma/ackr3a mutations alter cardiac lymphatics and neutrophil clearance; hypothesis-generating for human regeneration, no practice change.
Cardiac lymphatics regulate fluid homeostasis and immune cell clearance. The mechanisms underlying cardiac lymphatic vessel formation remain unclear. We perform spatial transcriptomics on the zebrafish heart at the single-cell level and investigate gene expression patterns in cardiac lymphatic endothelial cells (LECs). adrenomedullin a (adma) is mainly expressed in the epicardium adjacent to cardiac lymphatics. adma mutants develop edema and dilated outflow tracts with mis-patterned and reduced lymphatics, while their ventricular lymphatics are dilated with fewer sprouts, increased lyve1b expression, and altered lymphatic subpopulation composition. Loss of ackr3a, which encodes an Adm decoy receptor, increases lymphatic sprouts. During heart regeneration, adma and ackr3a are expressed in epicardium-derived cells within the wound. Neutrophil clearance is reduced in adma mutants but increased in ackr3a mutants. Our findings uncover the heterogeneity of cardiac LECs and show that Adm and Ackr3 regulate cardiac lymphatic vessel formation in the zebrafish heart. Here they use spatial transcriptomics to analyze cardiac lymphatic endothelial cells in zebrafish heart and show that adrenomedullin a and ackr3a are critical in cardiac lymphatic vessel development and immune cell clearance during regeneration.
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Feng et al. (2026) studied Cardiac lymphatic vessel formation and heart regeneration. adma and ackr3a CRISPR/Cas9 mutations vs. Wild-type (WT) sibling controls was evaluated on Ventricular lymphatic sprouts (tips with filopodia) (decreased by 80% in male and 66.2% in female adma mutants). Mutation of adma reduced ventricular lymphatic sprouts by up to 80% and impaired neutrophil clearance, whereas mutation of ackr3a increased lymphatic sprouting and accelerated neutrophil clearance in the zebrafish heart.
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