Generation of the Epicardial Lineage from Human Pluripotent Stem Cells

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2014 Sep 22

PMID 25240927

Citations 99

Authors

Alec D Witty

Anton Mihic

Roger Y Tam

Stephanie A Fisher

Alexander Mikryukov

Molly S Shoichet

Ren-Ke Li

Steven J Kattman

Gordon Keller

Affiliations

Soon will be listed here.

Abstract

The epicardium supports cardiomyocyte proliferation early in development and provides fibroblasts and vascular smooth muscle cells to the developing heart. The epicardium has been shown to play an important role during tissue remodeling after cardiac injury, making access to this cell lineage necessary for the study of regenerative medicine. Here we describe the generation of epicardial lineage cells from human pluripotent stem cells by stage-specific activation of the BMP and WNT signaling pathways. These cells display morphological characteristics and express markers of the epicardial lineage, including the transcription factors WT1 and TBX18 and the retinoic acid-producing enzyme ALDH1A2. When induced to undergo epithelial-to-mesenchymal transition, the cells give rise to populations that display characteristics of the fibroblast and vascular smooth muscle lineages. These findings identify BMP and WNT as key regulators of the epicardial lineage in vitro and provide a model for investigating epicardial function in human development and disease.

Citing Articles

Human epicardial organoids from pluripotent stem cells resemble fetal stage with potential cardiomyocyte- transdifferentiation.

Wang F, Zou X, Zheng H, Kong T, Pei D Cell Biosci. 2025; 15(1):4.

PMID: 39825425 PMC: 11740338. DOI: 10.1186/s13578-024-01339-w.

The pericardium forms as a distinct structure during heart formation.

Moran H, Nyarko O, ORourke R, Ching R, Riemslagh F, Pena B bioRxiv. 2024; .

PMID: 39345600 PMC: 11429720. DOI: 10.1101/2024.09.18.613484.

SMAD3 mediates the specification of human induced pluripotent stem cell-derived epicardium into progenitors for the cardiac pericyte lineage.

Miyoshi Y, Lucena-Cacace A, Tian Y, Matsumura Y, Tani K, Nishikawa M Stem Cell Reports. 2024; 19(10):1399-1416.

PMID: 39332407 PMC: 11561457. DOI: 10.1016/j.stemcr.2024.08.008.

Efficient and reproducible generation of human iPSC-derived cardiomyocytes and cardiac organoids in stirred suspension systems.

Prondzynski M, Berkson P, Trembley M, Tharani Y, Shani K, Bortolin R Nat Commun. 2024; 15(1):5929.

PMID: 39009604 PMC: 11251028. DOI: 10.1038/s41467-024-50224-0.

Exploring the Function of Epicardial Cells Beyond the Surface.

Wong D, Martinez J, Quijada P Circ Res. 2024; 135(2):353-371.

PMID: 38963865 PMC: 11225799. DOI: 10.1161/CIRCRESAHA.124.321567.

References

Smith C, Baek S, Sung C, Tallquist M . Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ Res. 2011; 108(12):e15-26. PMC: 3134964. DOI: 10.1161/CIRCRESAHA.110.235531. View

Watt A, Battle M, Li J, Duncan S . GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. Proc Natl Acad Sci U S A. 2004; 101(34):12573-8. PMC: 515098. DOI: 10.1073/pnas.0400752101. View

Mahtab E, Wijffels M, van den Akker N, Hahurij N, Lie-Venema H, Wisse L . Cardiac malformations and myocardial abnormalities in podoplanin knockout mouse embryos: Correlation with abnormal epicardial development. Dev Dyn. 2008; 237(3):847-57. DOI: 10.1002/dvdy.21463. View

Zhou B, Ma Q, Rajagopal S, Wu S, Domian I, Rivera-Feliciano J . Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature. 2008; 454(7200):109-13. PMC: 2574791. DOI: 10.1038/nature07060. View

Xavier-Neto J, Shapiro M, Houghton L, Rosenthal N . Sequential programs of retinoic acid synthesis in the myocardial and epicardial layers of the developing avian heart. Dev Biol. 2000; 219(1):129-41. DOI: 10.1006/dbio.1999.9588. View

David R, Brenner C, Stieber J, Schwarz F, Brunner S, Vollmer M . MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat Cell Biol. 2008; 10(3):338-45. DOI: 10.1038/ncb1696. View

Smart N, Bollini S, Dube K, Vieira J, Zhou B, Davidson S . De novo cardiomyocytes from within the activated adult heart after injury. Nature. 2011; 474(7353):640-4. PMC: 3696525. DOI: 10.1038/nature10188. View

Dubois N, Craft A, Sharma P, Elliott D, Stanley E, Elefanty A . SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells. Nat Biotechnol. 2011; 29(11):1011-8. PMC: 4949030. DOI: 10.1038/nbt.2005. View

Komiyama M, Ito K, Shimada Y . Origin and development of the epicardium in the mouse embryo. Anat Embryol (Berl). 1987; 176(2):183-9. DOI: 10.1007/BF00310051. View

10.

Yang L, Soonpaa M, Adler E, Roepke T, Kattman S, Kennedy M . Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature. 2008; 453(7194):524-8. DOI: 10.1038/nature06894. View

11.

Liu J, Stainier D . Tbx5 and Bmp signaling are essential for proepicardium specification in zebrafish. Circ Res. 2010; 106(12):1818-28. PMC: 2892550. DOI: 10.1161/CIRCRESAHA.110.217950. View

12.

Limana F, Capogrossi M, Germani A . The epicardium in cardiac repair: from the stem cell view. Pharmacol Ther. 2010; 129(1):82-96. DOI: 10.1016/j.pharmthera.2010.09.002. View

13.

Yu P, Hong C, Sachidanandan C, Babitt J, Deng D, Hoyng S . Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2007; 4(1):33-41. PMC: 2727650. DOI: 10.1038/nchembio.2007.54. View

14.

von Gise A, Zhou B, Honor L, Ma Q, Petryk A, Pu W . WT1 regulates epicardial epithelial to mesenchymal transition through β-catenin and retinoic acid signaling pathways. Dev Biol. 2011; 356(2):421-31. PMC: 3147112. DOI: 10.1016/j.ydbio.2011.05.668. View

15.

Morabito C, Dettman R, Kattan J, Collier J, Bristow J . Positive and negative regulation of epicardial-mesenchymal transformation during avian heart development. Dev Biol. 2001; 234(1):204-15. DOI: 10.1006/dbio.2001.0254. View

16.

Casanova J, Travisano S, de la Pompa J . Epithelial-to-mesenchymal transition in epicardium is independent of Snail1. Genesis. 2012; 51(1):32-40. DOI: 10.1002/dvg.22353. View

17.

Cheung C, Bernardo A, Trotter M, Pedersen R, Sinha S . Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nat Biotechnol. 2012; 30(2):165-73. PMC: 3272383. DOI: 10.1038/nbt.2107. View

18.

Kattman S, Witty A, Gagliardi M, Dubois N, Niapour M, Hotta A . Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell. 2011; 8(2):228-40. DOI: 10.1016/j.stem.2010.12.008. View

19.

de la Cuesta F, Zubiri I, Maroto A, Posada M, Padial L, Vivanco F . Deregulation of smooth muscle cell cytoskeleton within the human atherosclerotic coronary media layer. J Proteomics. 2013; 82:155-65. DOI: 10.1016/j.jprot.2013.01.032. View

20.

Ma Q, Zhou B, Pu W . Reassessment of Isl1 and Nkx2-5 cardiac fate maps using a Gata4-based reporter of Cre activity. Dev Biol. 2008; 323(1):98-104. PMC: 2655699. DOI: 10.1016/j.ydbio.2008.08.013. View