Lymphoangiocrine signals promote cardiac growth and repair

Xiaolei Liu, Ester Cruz, Xiaowu Gu, Laszlo Balint, Michael Oxendine-Burns, Tamara Terrones, Wanshu Ma, Hui-Hsuan Kuo, Connor Lantz, Trisha Bansal, Edward Thorp, Paul Burridge, Zoltán Jakus, Joachim Herz, Ondine Cleaver, Miguel Torres and Guillermo Oliver ()
Additional contact information
Xiaolei Liu: Northwestern University
Ester Cruz: Cardiovascular Development Program, Centro Nacional de Investigaciones Cardiovasculares, CNIC
Xiaowu Gu: University of Texas Southwestern Medical Center
Laszlo Balint: Semmelweis University School of Medicine
Michael Oxendine-Burns: Northwestern University
Tamara Terrones: University of Texas Southwestern Medical Center
Wanshu Ma: Northwestern University
Hui-Hsuan Kuo: Northwestern University
Connor Lantz: Northwestern University
Trisha Bansal: Northwestern University
Edward Thorp: Northwestern University
Paul Burridge: Northwestern University
Zoltán Jakus: Semmelweis University School of Medicine
Joachim Herz: University of Texas Southwestern Medical Center
Ondine Cleaver: University of Texas Southwestern Medical Center
Miguel Torres: Cardiovascular Development Program, Centro Nacional de Investigaciones Cardiovasculares, CNIC
Guillermo Oliver: Northwestern University

Nature, 2020, vol. 588, issue 7839, 705-711

Abstract: Abstract Recent studies have suggested that lymphatics help to restore heart function after cardiac injury1–6. Here we report that lymphatics promote cardiac growth, repair and cardioprotection in mice. We show that a lymphoangiocrine signal produced by lymphatic endothelial cells (LECs) controls the proliferation and survival of cardiomyocytes during heart development, improves neonatal cardiac regeneration and is cardioprotective after myocardial infarction. Embryos that lack LECs develop smaller hearts as a consequence of reduced cardiomyocyte proliferation and increased cardiomyocyte apoptosis. Culturing primary mouse cardiomyocytes in LEC-conditioned medium increases cardiomyocyte proliferation and survival, which indicates that LECs produce lymphoangiocrine signals that control cardiomyocyte homeostasis. Characterization of the LEC secretome identified the extracellular protein reelin (RELN) as a key component of this process. Moreover, we report that LEC-specific Reln-null mouse embryos develop smaller hearts, that RELN is required for efficient heart repair and function after neonatal myocardial infarction, and that cardiac delivery of RELN using collagen patches improves heart function in adult mice after myocardial infarction by a cardioprotective effect. These results highlight a lymphoangiocrine role of LECs during cardiac development and injury response, and identify RELN as an important mediator of this function.

Date: 2020
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DOI: 10.1038/s41586-020-2998-x

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