Lymphoangiocrine signals promote cardiac growth and repair

Abstract

Recent studies suggested a beneficial role of lymphatics in restoring heart function after cardiac injury 1 – 6 . Here we report that in mice lymphatics promote cardiac growth, repair and cardio-protection. We show that a lymphoangiocrine signal produced by lymphatic endothelial cells (LECs) controls cardiomyocyte (CM) proliferation and survival during heart development, improves neonatal cardiac regeneration and is cardioprotective after myocardial infarction (MI). Embryos devoid of LECs develop smaller hearts as a consequence of reduced CM proliferation and increased CM apoptosis. Culturing primary mouse CMs in LEC-conditioned media increases CM proliferation and survival, indicating that LECs produce lymphoangiocrine signals controlling CM homeostasis. Characterization of the LEC secretome identified Reelin as a key player responsible for such function. Moreover, we report that LEC-specific Reln -null embryos also develop smaller hearts, that Reelin is required for efficient heart repair and function following neonatal MI, and that cardiac delivery of REELIN using collagen patches improves adult heart function after MI through a cardioprotective effect. These results identify a lymphoangiocrine role of LECs during cardiac development and injury response, and Reelin as an important mediator of this function.

The Lymphatic System in Zebrafish Heart Development, Regeneration and Disease Modeling

“…Besides its physiologic function in MI, the cardiac lymphatic vessels also secrete signal molecules in regulating heart repair. Lui et al have shown that Reelin (RELN), an extracellular matrix protein mainly expressed by cardiac LECs, regulates heart growth and promotes cardiomyocyte (CM) proliferation during development in mice hearts [ 78 ]. During heart repair in neonatal mice, Reln expression was highly induced at the injury site [ 78 ].…”

“…Lui et al have shown that Reelin (RELN), an extracellular matrix protein mainly expressed by cardiac LECs, regulates heart growth and promotes cardiomyocyte (CM) proliferation during development in mice hearts [ 78 ]. During heart repair in neonatal mice, Reln expression was highly induced at the injury site [ 78 ]. The deletion of RELN diminished the heart repair with increased scar size and reduced heart function [ 78 ].…”

“…During heart repair in neonatal mice, Reln expression was highly induced at the injury site [ 78 ]. The deletion of RELN diminished the heart repair with increased scar size and reduced heart function [ 78 ]. Consistent with its role in heart development, CM proliferation was reduced and CM apoptosis elevated in Reln mutants after MI.…”

“…They appear in zebrafish heart during regeneration after cryoinjury [ 34 ]. Furthermore, the identification of the first lymphangiocrine, RELN, suggests that the positive benefits post-MI are not limited to the lymphatics acting as a conduit in the classical sense [ 78 ]. Individual cells could excrete pro-regenerative factors or provide scavenger functions much like those described of brain LECs/fluorescent granular perithelial cells [ 82 , 83 ].…”

“…In most conditions of compromised Vegfc-Flt4 and/or coronary vessel signaling, the BA lymphatic vessels remain largely unaffected, and this may be sufficient to provide a conduit for fluid removal. It remains to be determined if the hypertrophy observed in the vegfc hypermorph; vegfd double mutant ( vegfc hy−/− ; vegfd −/− ) is due to loss of the BA populations, misregulation of Flt4/Vegfr3-independent signaling or a compensatory effect of earlier reductions in cardiomyocyte proliferation due to loss of mitogens as observed in the mouse [ 78 ]. The phenotypic variability observed with the vegfc hy−/− ; vegfd −/− combination, indeed all the variability in reported phenotypes across the three studies using various mutant alleles and reporters, needs to be considered in light of varying modifiers in the genetic background [ 91 ].…”