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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 705-711 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 588 |
| Issue number | 7839 |
| DOIs | |
| State | Published - Dec 24 2020 |
Funding
Acknowledgements This work was supported by NIH grant (RO1HL073402-16) to G.O., AHA grant (18CDA34110356) to X.L., 5T32HL134633 to W.M., FPU grant from the Spanish Ministry of Education, Culture and Sports and EMBO Short-Term Fellowship to E.D.C., Leducq TNE-17CVD and RD16/0011/0019 (ISCIII) from the Spanish Ministry of Science, Innovation, and Universities to M.T., NIH T32 GM008061 to C.L., HL63762, and NS093382 to J.H. We thank G. M. Rune and B. Brunne for the Reln+/− strain. RNA-seq work was supported by the Northwestern University NUSeq Core Facility. We thank the Robert H. Lurie Cancer Center Flow Cytometry facility supported by NCI CCSG P30 CA060553 for their invaluable assistance. Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system and BD FACSymphony S6 SORP system, purchased through the support of NIH 1S10OD011996-01 and 1S10OD026814-01. Imaging work was performed at the Northwestern University Center for Advanced Microscopy supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Spinning disk confocal microscopy was performed on an Andor XDI Revolution microscope, purchased through the support of NCRR 1S10 RR031680-01. Proteomics services were performed by the Northwestern Proteomics Core Facility supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. We thank the George M. O’Brien Kidney Research Core Center (NU GoKidney, supported by a P30 DK114857 award from NIDDK) for the use of the Echocardiography machine. The myocardial infarction surgeries were performed by the comprehensive Transplant Center Microsurgery Core, partially supported by NIH NIAID P01AI112522. We thank J. Jin and P. Liu for help with the ELISA reagents and data analysis, R. Ma for help with DNA polyploidy analysis, A. Shi for the MEF2C antibodies, M. Dellinger for the Prox1-creERT2 mice and H. Ardehali for the Myh6-cre mice. We specially thank B. Sosa-Pineda for advice and suggestions and P. Ruiz-Lozano for sharing her expertise in the preparation of the collagen patches.
ASJC Scopus subject areas
- General
