Cardiac Muscle Cell Formation

Leader: Maurice van den Hoff

Expertise

Heart muscle cell formation

The research line "heart muscle cell formation" focuses on cardiac development after formation of the linear heart tube. A 3-dimensional gel lattice in vitro explant system has been developed in which heart muscle and epicardial development can be mimicked, manipulated and analyzed using confocal laser scanning microscopy. In vitro and in vivo heart development is influenced by applying growth factors and/or using recombinant adenoviruses. The recombinant adenoviruses are developed and produced within the group and comprise an extensive collection of constitutive active and dominant negative acting components of the BMP signalling pathway. Research focuses on heart muscle cell formation at the inflow of the heart, at the level of the proepicardium. Candidate gene analyses have identified an integrated role of BMP and FGF signalling. Concomitantly, an extensive genome wide analysis using chicken microarrays has been preformed, pointing not only to a role for BMP and FGF signalling, but also for Wnt signalling, which is currently being pursued. Using the genetic lineage tracing technique, Cre-loxP system, the endocardial, epicardial and neural crest lineages contributing to the heart are being re-evaluated and studied during development and disease using the mTomato/mGFP reporter mouse line. This mT/mG reporter appears to be more sensitive and has a much better spatial resolution than the previously used lacZ reporter line, allowing a more adequate analysis of the different cardiac structure and cell types. These genome-wide analyses have also identified novel candidates that are potential regulators of heart muscle cell and epicardium formation. The most promising candidate of which was Follistatin-like 1 (Fstl1). We have prepared a general and conditional knock-out of Fstl1. The general knock-out was found to have a severe phenotype, dying at birth due to respiratory distress. Functional disruption of Fstl1 in the cardiomyocytes was found to attenuate hypertrophy following pressure overload. Fstl1 was found to be transiently and highly expressed in the infarct after a myocardial infarction. The role of Fstl1 in the different cell populations of the heart is currently being studied during development and disease.

Collaborations

The development of the heart with respect to myocardial differentiation and epicardial development is studied in collaboration with the groups of Prof.dr. Roger Markwald and Prof dr. Andy Wessels in the Medical University of South Carolina, Charleston, SC, USA, and dr. José Maria Pérez-Pomares, University of Malaga, Spain.

The genome wide studies are performed in collaboration with Peter-Bram ‘t Hoen of the department of human genetics, Leiden University Medical Center, The Netherlands.

The lung phenotype of the Fstl1 knock out is studied in collaboration with Prof dr. Martina Schmidt of the department Molecular Pharmacology, Groningen University, The Netherlands.

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SELECTED PUBLICATIONS

Wessels A, van den Hoff MJ, Adamo RF, Phelps AL, Lockhart MM, Sauls K, Briggs LE, Norris RA, van Wijk B, Perez-Pomares JM, Dettman RW, Burch JB. Epicardially derived fibroblasts preferentially contribute to the parietal leaflets of the atrioventricular valves in the murine heart. Dev Biol. 2012;366:111-124.

Shimano M, Ouchi N, Nakamura K, van Wijk B, Ohashi K, Asaumi Y, Higuchi A, Pimentel DR, Sam F, Murohara T, van den Hoff MJ, Walsh K. Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload. Proc Natl Acad Sci U S A. 2011;108:E899-906

Sylva M, Li VS, Buffing AA, van Es JH, van den Born M, van der Velden S, Gunst Q, Koolstra JH, Moorman AF, Clevers H, van den Hoff MJ. The BMP antagonist follistatin-like 1 is required for skeletal and lung organogenesis. PLoS One. 2011;6:e22616.

Buermans HP, van Wijk B, Hulsker MA, Smit NC, den Dunnen JT, van Ommen GB, Moorman AF, van den Hoff MJ, 't Hoen PA. Comprehensive gene-expression survey identifies wif1 as a modulator of cardiomyocyte differentiation. PLoS One. 2010;5:e15504.

van Wijk B, van den Berg G, Abu-Issa R, Barnett P, van der Velden S, Schmidt M, Ruijter JM, Kirby ML, Moorman AFM, van den Hoff MJB, Epicardium and Myocardium Separate From a Common Precursor Pool by Crosstalk Between Bone Morphogenetic Protein- and Fibroblast Growth Factor-Signaling Pathways. Circ Res 2009;105:431-437

van den Berg G, Abu-Issa R, de Boer BA, Hutson MR, de Boer PAJ, Soufan AT, Ruijter JM, Kirby ML, van den Hoff MJB, Moorman AFM, A caudal proliferating growth center contributes to both poles of the forming heart tube. CIRC RES 2009;104 (2):179-188

van Wijk B, Moorman AFM, van den Hoff MJB, Role of bone morphogenetic proteins in cardiac differentiation. Cardiovasc Res 2007;74 (2):244-255

Team members

namefunction
Maurice van den HoffGroup Leader (PI)
Adrian Ruiz-VillalbaScientist
Andrea MattiottiPhD student
Stuti PrakashPhD student
Anita BuffingTechnician
Quinn GunstTechnician
Laura van Os-GaldosStudent
Jur GerritsenStagiaire HBO

Key publications