The role of Meis transcription factors in the epicardium
Advisor
Torres Sánchez, MiguelEntity
UAM. Departamento de Biología Molecular; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Date
2021-07-23Funded by
This study was funded by grants RD12/0019/0005 and RD16/0011/0019 (TerCel, RETICS); S2010-BMD-2315 (Comunidad de Madrid); BFU2012-31086 (MINECO); BFU2015-71519 (MEIC); PGC2018-096486-B-I00 (MICINN) and ref. 17CVD04 (Leducq Foundation Transatlantic Networks).Subjects
Epicardio; Factores de transcripción; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 23-07-2021Esta tesis tiene embargado el acceso al texto completo hasta el 23-01-2023

Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
A single layer of cells could be perceived as insignificant in comparison to a whole organ. However,
extensive evidence has shown that the epicardium, the outermost layer of the heart, is essential for
cardiac development and regeneration. Epicardial-derived cells (EPDCs) and epicardial signalling are
crucial for coronary vasculature development and myocardial growth. In this thesis, we show that
MEIS homeodomain transcription factors are expressed and play a function in the epicardium during
cardiac development. Meis1 and Meis2 epicardial-specific conditional mutant mice show 50% lethality
associated to misalignment of the great vessels and die after birth, while the survivors do not show
cardiac malformations. Epicardial epithelial-to-mesenchymal transition of epicardial cells is relatively
unaffected in Meis mutants, but EPDCs specification is altered, resulting in an excess of myofibroblast
differentiation in detriment of smooth muscle cell (SMC) and other fibroblast populations. The
excess myofibroblasts observed in Meis mutants accumulate in the subepicardium. Retinoic acid
signalling is a major signalling pathway in the epicardium and is strongly impaired in the mutants,
which could account for the altered specification of EPDCs. Decreased SMC coverage leads to a
delayed maturation of the blood coronary vasculature, which also shows patterning alterations.
Further characterization of Meis1 and Meis2 epicardial-specific conditional mutants has
revealed the failure of prenatal lymphatic vessel development. This reveals a previously unknown
non-autonomous function of the epicardium in promoting cardiac lymphangiogenesis. We
characterize a population of subepicardial, fibroblast-like Lymphatic-associated EPDCs (LEPCs) that
completely enseaths lymphatic vessels as they grow towards the apex of the ventricles. LEPDC and
Lymphatic Endothelial Cell (LECs) association is disrupted in Meis mutants, which suggests that
LEPDC-LEC crosstalk is important for cardiac lymphangiogenesis. Transcriptomic analysis of Meismutant
epicardium/subepicardium showed a downregulation of Vegfc and Vegfd lymphoangiocrine
signals. Epicardial-specific Vegfc mutants present less developed and immature coronary lymphatic
vessels, whereas analysis of the lymphatic vasculature of Vegfd knockout hearts shows that VEGFD
is important for the development of ventral coronary lymphatics. These results show that direct
cellular interactions and paracrine signalling from the epicardium/EPDCs orchestrate cardiac
lymphatic development and that this process is regulated by MEIS transcription factors
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Google Scholar:Cruz Crespillo, Mª Ester de la
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