TY - JOUR
T1 - Lymphoangiocrine signals promote cardiac growth and repair
AU - Liu, Xiaolei
AU - De la Cruz, Ester
AU - Gu, Xiaowu
AU - Balint, Laszlo
AU - Oxendine-Burns, Michael
AU - Terrones, Tamara
AU - Ma, Wanshu
AU - Kuo, Hui Hsuan
AU - Lantz, Connor
AU - Bansal, Trisha
AU - Thorp, Edward
AU - Burridge, Paul
AU - Jakus, Zoltán
AU - Herz, Joachim
AU - Cleaver, Ondine
AU - Torres, Miguel
AU - Oliver, Guillermo
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/12/24
Y1 - 2020/12/24
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-020-2998-x
DO - 10.1038/s41586-020-2998-x
M3 - Article
C2 - 33299187
AN - SCOPUS:85097304312
SN - 0028-0836
VL - 588
SP - 705
EP - 711
JO - Nature
JF - Nature
IS - 7839
ER -