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The pro-epicardium develops from lateral plate mesoderm progenitors, next to septum transversum mesenchyme, a structure deeply involved in liver embryogenesis. Here we describe a self-organized human multilineage organoid that recreates the co-emergence of pro-epicardium, septum transversum mesenchyme and liver bud. Additionally, we study the impact of WNT, BMP and retinoic acid signaling modulation on multilineage organoid specification. By co-culturing these organoids with cardiomyocyte aggregates, we generated a self-organized heart organoid comprising an epicardium-like layer that fully surrounds \u00a0a myocardium-like tissue. These heart organoids recapitulate the impact of epicardial cells on promoting cardiomyocyte proliferation and structural and functional maturation. Therefore, the human heart organoids described herein, open the path to advancing knowledge on how myocardium-epicardium interaction progresses during heart organogenesis in healthy or diseased settings.<\/jats:p>","DOI":"10.1038\/s41467-022-34730-7","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T19:06:57Z","timestamp":1668539217000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Human multilineage pro-epicardium\/foregut\u00a0organoids support the development of an\u00a0epicardium\/myocardium organoid"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9795-3323","authenticated-orcid":false,"given":"Mariana A.","family":"Branco","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9133-8856","authenticated-orcid":false,"given":"Tiago P.","family":"Dias","sequence":"additional","affiliation":[]},{"given":"Joaquim M. S.","family":"Cabral","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6477-6030","authenticated-orcid":false,"given":"Perpetua","family":"Pinto-do-\u00d3","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6270-4455","authenticated-orcid":false,"given":"Maria Margarida","family":"Diogo","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,11,15]]},"reference":[{"key":"34730_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25329-5","volume":"12","author":"YR Lewis-Israeli","year":"2021","unstructured":"Lewis-Israeli, Y. R. et al. Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease. Nat. Commun. 12, 5142 (2021).","journal-title":"Nat. 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Smooth muscle cells and fibroblasts of the coronary arteries derive from epithelial-mesenchymal transformation of the epicardium. Anat. Embryol. 199, 367\u2013378 (1999).","journal-title":"Anat. Embryol."},{"key":"34730_CR8","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.ydbio.2012.04.020","volume":"366","author":"A Wessels","year":"2012","unstructured":"Wessels, A. et al. Epicardially derived fibroblasts preferentially contribute to the parietal leaflets of the atrioventricular valves in the murine heart. Dev. Biol. 366, 111\u2013124 (2012).","journal-title":"Dev. Biol."},{"key":"34730_CR9","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/nature06969","volume":"454","author":"C-L Cai","year":"2008","unstructured":"Cai, C.-L. et al. A myocardial lineage derives from Tbx18 epicardial cells. 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Spatiotemporal analysis reveals overlap of key proepicardial markers in the developing murine heart. Stem Cell Rep. 14, 770\u2013787 (2020).","journal-title":"Stem Cell Rep."},{"key":"34730_CR13","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1242\/dev.054239","volume":"138","author":"T Brade","year":"2011","unstructured":"Brade, T. et al. Retinoic acid stimulates myocardial expansion by induction of hepatic erythropoietin which activates epicardial Igf2. Development 138, 139\u2013148 (2011).","journal-title":"Development"},{"key":"34730_CR14","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1242\/dev.054338","volume":"138","author":"P Li","year":"2011","unstructured":"Li, P. et al. IGF signaling directs ventricular cardiomyocyte proliferation during embryonic heart development. 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