DMH1, a Novel BMP Small Molecule Inhibitor, Increases Cardiomyocyte Progenitors and Promotes Cardiac Differentiation in Mouse Embryonic Stem Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Aug 1

PMID 22848549

Citations 25

Authors

Ada Ao

Jijun Hao

Corey R Hopkins

Charles C Hong

Affiliations

Soon will be listed here.

Abstract

The possibility of using cell-based therapeutics to treat cardiac failure has generated significant interest since the initial introduction of stem cell-based technologies. However, the methods to quickly and robustly direct stem cell differentiation towards cardiac cell types have been limited by a reliance on recombinant growth factors to provide necessary biological cues. We report here the use of dorsomorphin homologue 1 (DMH1), a second-generation small molecule BMP inhibitor based on dorsomorphin, to efficiently induce beating cardiomyocyte formation in mouse embryonic stem cells (ESCs) and to specifically upregulate canonical transcriptional markers associated with cardiac development. DMH1 differs significantly from its predecessor by its ability to enrich for pro-cardiac progenitor cells that respond to late-stage Wnt inhibition using XAV939 and produce secondary beating cardiomyocytes. Our study demonstrates the utility of small molecules to complement existing in vitro cardiac differentiation protocols and highlights the role of transient BMP inhibition in cardiomyogenesis.

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References

Li W, Ding S . Small molecules that modulate embryonic stem cell fate and somatic cell reprogramming. Trends Pharmacol Sci. 2009; 31(1):36-45. DOI: 10.1016/j.tips.2009.10.002. View

Qyang Y, Martin-Puig S, Chiravuri M, Chen S, Xu H, Bu L . The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway. Cell Stem Cell. 2008; 1(2):165-79. DOI: 10.1016/j.stem.2007.05.018. View

Hill C, Sanchez N, Love J, Arrieta J, Hong C, Brown C . BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFβ receptor to promote invasion. Cell Signal. 2012; 24(5):1012-22. PMC: 3288519. DOI: 10.1016/j.cellsig.2011.12.022. View

McMahon A, Bradley A . The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell. 1990; 62(6):1073-85. DOI: 10.1016/0092-8674(90)90385-r. View

Wang H, Hao J, Hong C . Cardiac induction of embryonic stem cells by a small molecule inhibitor of Wnt/β-catenin signaling. ACS Chem Biol. 2010; 6(2):192-7. PMC: 3076310. DOI: 10.1021/cb100323z. View

Ueno S, Weidinger G, Osugi T, Kohn A, Golob J, Pabon L . Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proc Natl Acad Sci U S A. 2007; 104(23):9685-90. PMC: 1876428. DOI: 10.1073/pnas.0702859104. View

Liu W, Foley A . Signaling pathways in early cardiac development. Wiley Interdiscip Rev Syst Biol Med. 2010; 3(2):191-205. DOI: 10.1002/wsbm.112. View

Paige S, Osugi T, Afanasiev O, Pabon L, Reinecke H, Murry C . Endogenous Wnt/beta-catenin signaling is required for cardiac differentiation in human embryonic stem cells. PLoS One. 2010; 5(6):e11134. PMC: 2886114. DOI: 10.1371/journal.pone.0011134. View

Schultheiss T, Burch J, Lassar A . A role for bone morphogenetic proteins in the induction of cardiac myogenesis. Genes Dev. 1997; 11(4):451-62. DOI: 10.1101/gad.11.4.451. View

10.

Yuasa S, Itabashi Y, Koshimizu U, Tanaka T, Sugimura K, Kinoshita M . Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells. Nat Biotechnol. 2005; 23(5):607-11. DOI: 10.1038/nbt1093. View

11.

Hao J, Daleo M, Murphy C, Yu P, Ho J, Hu J . Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells. PLoS One. 2008; 3(8):e2904. PMC: 2483414. DOI: 10.1371/journal.pone.0002904. View

12.

Fuegemann C, Samraj A, Walsh S, Fleischmann B, Jovinge S, Breitbach M . Differentiation of mouse embryonic stem cells into cardiomyocytes via the hanging-drop and mass culture methods. Curr Protoc Stem Cell Biol. 2010; Chapter 1:Unit 1F.11. DOI: 10.1002/9780470151808.sc01f11s15. 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.

Marques S, Yelon D . Differential requirement for BMP signaling in atrial and ventricular lineages establishes cardiac chamber proportionality. Dev Biol. 2009; 328(2):472-82. PMC: 2709526. DOI: 10.1016/j.ydbio.2009.02.010. View

15.

Lough J, Barron M, Brogley M, Sugi Y, Bolender D, Zhu X . Combined BMP-2 and FGF-4, but neither factor alone, induces cardiogenesis in non-precardiac embryonic mesoderm. Dev Biol. 1996; 178(1):198-202. DOI: 10.1006/dbio.1996.0211. View

16.

Cross E, Thomason R, Martinez M, Hopkins C, Hong C, Bader D . Application of small organic molecules reveals cooperative TGFβ and BMP regulation of mesothelial cell behaviors. ACS Chem Biol. 2011; 6(9):952-61. PMC: 3177035. DOI: 10.1021/cb200205z. View

17.

Barron M, Gao M, Lough J . Requirement for BMP and FGF signaling during cardiogenic induction in non-precardiac mesoderm is specific, transient, and cooperative. Dev Dyn. 2000; 218(2):383-93. DOI: 10.1002/(SICI)1097-0177(200006)218:2<383::AID-DVDY11>3.0.CO;2-P. View

18.

Fehling H, Lacaud G, Kubo A, Kennedy M, Robertson S, Keller G . Tracking mesoderm induction and its specification to the hemangioblast during embryonic stem cell differentiation. Development. 2003; 130(17):4217-27. DOI: 10.1242/dev.00589. View

19.

Tirosh-Finkel L, Zeisel A, Brodt-Ivenshitz M, Shamai A, Yao Z, Seger R . BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors. Development. 2010; 137(18):2989-3000. DOI: 10.1242/dev.051649. View

20.

Puceat M . Protocols for cardiac differentiation of embryonic stem cells. Methods. 2008; 45(2):168-71. DOI: 10.1016/j.ymeth.2008.03.003. View