Cardiac lymphatics are heterogeneous in origin and respond to injury

Abstract

The lymphatic vasculature is a blind-ended network crucial for tissue fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. In contrast, we reveal here that cardiac lymphatic vessels have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple cre-lox based lineage tracing revealed a potential contribution from the hemogenic endothelium during development and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2+ and Vav1+ compartments. In the adult heart, myocardial infarction (MI) promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury.

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

“…Lymphangiogenesis occurs after MI 35. Enhancement of lymphangiogenesis may reduce myocardial oedema and cardiac fibrosis, promoting improvement in cardiac function 36, 37. Our data show that lymphatic capillaries in the infarcted heart increased in cell patch group than that in patch‐ or MSC‐only groups.…”

Pdgfrb‐Cre targets lymphatic endothelial cells of both venous and non‐venous origins

“…3a). This is consistent with recently published data showing Pdgfrb‐Cre mediated targeting of ECs within the cardinal vein, JLS and lymphovenous valves (Turner et al, 2014), but is in contrast to findings of Klotz et al ., (2015) reporting absence of Pdgfrb‐Cre mediated recombination within the E10 cardinal vein and E12.5 JLS (Klotz et al, 2015). FACS analysis of endothelial cells (Fig.…”

“…We (Stanczuk et al ., 2015) and others (Klotz et al ., 2015) recently showed that Pdgfrb‐Cre unexpectedly also targets a large proportion of embryonic lymphatic endothelial cells (LECs) in the developing mesentery (Stanczuk et al ., 2015) and the heart (Klotz et al ., 2015). These observations were made in the context of the startling discovery that LECs in the heart (Klotz et al ., 2015), mesentery (Stanczuk et al .…”

“…We (Stanczuk et al ., 2015) and others (Klotz et al ., 2015) recently showed that Pdgfrb‐Cre unexpectedly also targets a large proportion of embryonic lymphatic endothelial cells (LECs) in the developing mesentery (Stanczuk et al ., 2015) and the heart (Klotz et al ., 2015). These observations were made in the context of the startling discovery that LECs in the heart (Klotz et al ., 2015), mesentery (Stanczuk et al . 2015), and skin (Martinez‐Corral et al ., 2015), not only develop through lymphangiogenic sprouting from a venous blood vascular source, which has previously been the only known mechanism for lymphatic vessel formation in mammals (Srinivasan et al ., 2007), but also through the assembly of nonvenous derived LEC progenitors.…”

“…Based on the highly efficient ability of Pdgfrb‐Cre to target non‐venous derived mesenteric LECs and lymphatic vessels (Stanczuk et al, 2015), along with the suggested YS HemEC origin of the Pdgfrb‐Cre labeled LECs in the heart (Klotz et al, 2015), we set out to carefully evaluate the suggested ability of Pdgfrb‐Cre to trace YS‐derived HemEC‐progenitors (Klotz et al, 2015) and its potential as a specific lineage marker for non‐venous derived LEC progenitors. Here we demonstrate that Pdgfrb‐Cre is not a valid tool for tracing YS HemEC‐activity or YS derived progenitors, showing minimal expression in YS ECs before E12 and no tracing of the early YS‐derived myeloid lineages.…”