What is the role of mechanics in cardiac development?2018-07-02T12:15:28+08:30

What is the role of mechanics in cardiac development?

The various events during cardiac development are driven by mechanical signals sensed through cellular communication with its immediate environment, which include both the extracellular matrix as well as intercellular cell-cell contacts. These signals can induce the generation of intracellular forces through large-scale cytoskeletal reorganization, which may again influence the mechanical properties of the extracellular environment. For instance, during the process of endocardial tube formation, the movement of the bilateral heart fields towards the embryonic midline involves the migration of lateral mesodermal cells over the underlying endoderm. The migration of the mesoderm is dependent on a morphogenetic event called endodermal shortening, which occurs around the anterior intestinal portal. The large-scale tissue deformations caused by the shortening of endodermal cells generates tension that pulls the mesoderm cells towards the embryonic midline. It is now known that endodermal shortening is mediated by actomyosin-dependent cellular contractility, as these morphogenetic events are disrupted in the presence of blebbistatin, a myosin-II inhibitor [1].

Another event in cardiac development that requires changes to cell morphology is the ballooning of the heart chambers. This process involves the expansion and bulging of the walls of the heart tube in such a way that the chambers develop into a bean-shaped structure, with the outer walls taking on a convex curvature and the inner walls becoming concave. A study using high resolution imaging to study cell shape changes in Zebrafish embryo hearts has revealed that the cells of the inner wall maintain a cuboidal shape while the cells of the outer wall flatten and elongate, giving rise to the characteristic bean-shape of the heart chambers. Interestingly, distinct cellular morphologies in the inner and outer wall regions was found to arise as a result of net effect of wall shear forces from circulating blood and contractile forces from intracellular cytoskeletal dynamics [2][3][4].

A biomechanical basis has also been posited for the formation of the heart tube based upon the fusion of two primordial epithelial tubes. According to this theory, actin filaments near the apical surfaces of the cardiac progenitor cells contract, so that the cells become wedge-shaped. As the apical surfaces of neighboring cells curve inwards, it leads to the cylindrical bending of a sheet of epithelial cells. These tissue-level deformations are believed to result in the formation of the cardiac tube [5][6]. In support of this hypothesis, confocal laser scanning microscopy studies have confirmed the arrangement of actin filaments near the apices of early cardiac epithelial cells [7]. Also, during the process of looping, the tubular heart undergoes various mechanical alterations such as bending and rotational movements before attaining a mature S-shape. From a number of studies, it is now posited that while actin polymerization-mediated shape changes in cardiac epithelial cells drives the bending of the heart tube, the rotational movements are driven by a combination of forces exerted on the heart tube by its encapsulating membrane called the splanchnopleure as well as from contraction of the intracellular cytoskeleton [8][9][10].

Although cardiac contractions begin very early in the evolving heart tube and blood flow is established soon after looping, the circulating blood does not yet serve the function of transporting gases, nutrients, and metabolic wastes within the developing embryo, which at this stage is still carried out by passive diffusion. However, the hemodynamic forces generated from the circulating blood was found to be essential for inducing proper cardiac development and active remodeling of the cardiac vessels, including the valves and the great blood vessels. This is evident from presentations of cardiac abnormalities in Zebrafish embryos, such as diminished looping and impaired valve formation, when either the inflow or the outflow tracts were occluded to reduce wall shear stress [11][12][13]. Given the significant role that biomechanical factors such as hemodynamic forces play in controlling cardiac morphogenesis, it is not surprising that a number of congenital cardiac diseases, such as the bicuspid aortic valve disease (BAV) and hypoplastic left heart syndrome (HLHS) are linked to abnormal flow patterns of circulating blood [14][15][16].

It is essential to understand the mechanistic details of cardiomyocyte differentiation and heart development in order to gain insights into the pathology of heart diseases, which account for almost 30% of global death [17]. One such major cardiovascular disease, myocardial infarction, involves a significant loss of cardiomyocytes due to oxygen and nutrient deficiency. However, development of effective therapies for cardiac tissue repair in such diseases remain challenging owing to the non-proliferative nature and extremely low regenerative potential of adult cardiomyocytes. This has resulted in massive research efforts geared towards generating cardiomyocytes from human embryonic stem cells as well as induced pluripotent stem cells under in vitro conditions, which could be used to replenish cardiomyocyte number and volume post cardiac insult [18][17][19].

View All

Latest Findings

Protein Info


  1. Varner VD, and Taber LA. Not just inductive: a crucial mechanical role for the endoderm during heart tube assembly. Development 2012; 139(9):1680-90. [PMID: 22492358]
  2. Auman HJ, Coleman H, Riley HE, Olale F, Tsai H, and Yelon D. Functional modulation of cardiac form through regionally confined cell shape changes. PLoS Biol. 2007; 5(3):e53. [PMID: 17311471]
  3. Hierck BP, Van der Heiden K, Poelma C, Westerweel J, and Poelmann RE. Fluid shear stress and inner curvature remodeling of the embryonic heart. Choosing the right lane! ScientificWorldJournal 2008; 8:212-22. [PMID: 18661046]
  4. Gjorevski N, and Nelson CM. The mechanics of development: Models and methods for tissue morphogenesis. Birth Defects Res. C Embryo Today 2010; 90(3):193-202. [PMID: 20860059]
  5. Bartman T, and Hove J. Mechanics and function in heart morphogenesis. Dev. Dyn. 2005; 233(2):373-81. [PMID: 15830382]
  6. Keller R, Davidson LA, and Shook DR. How we are shaped: the biomechanics of gastrulation. Differentiation 2003; 71(3):171-205. [PMID: 12694202]
  7. Shiraishi I, Takamatsu T, Minamikawa T, and Fujita S. 3-D observation of actin filaments during cardiac myofibrinogenesis in chick embryo using a confocal laser scanning microscope. Anat. Embryol. 1992; 185(4):401-8. [PMID: 1609966]
  8. Manasek FJ, Burnside MB, and Waterman RE. Myocardial cell shape change as a mechanism of embryonic heart looping. Dev. Biol. 1972; 29(4):349-71. [PMID: 4120601]
  9. Nerurkar NL, Ramasubramanian A, and Taber LA. Morphogenetic adaptation of the looping embryonic heart to altered mechanical loads. Dev. Dyn. 2006; 235(7):1822-9. [PMID: 16607653]
  10. Taber LA, Voronov DA, and Ramasubramanian A. The role of mechanical forces in the torsional component of cardiac looping. Ann. N. Y. Acad. Sci. 2010; 1188:103-10. [PMID: 20201892]
  11. Granados-Riveron JT, and Brook JD. The impact of mechanical forces in heart morphogenesis. Circ Cardiovasc Genet 2012; 5(1):132-42. [PMID: 22337926]
  12. Hove JR, Köster RW, Forouhar AS, Acevedo-Bolton G, Fraser SE, and Gharib M. Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 2003; 421(6919):172-7. [PMID: 12520305]
  13. Lucitti JL, Jones EAV, Huang C, Chen J, Fraser SE, and Dickinson ME. Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development 2007; 134(18):3317-26. [PMID: 17720695]
  14. Bissell MM, Hess AT, Biasiolli L, Glaze SJ, Loudon M, Pitcher A, Davis A, Prendergast B, Markl M, Barker AJ, Neubauer S, and Myerson SG. Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type. Circ Cardiovasc Imaging 2013; 6(4):499-507. [PMID: 23771987]
  15. Lorenz R, Bock J, Barker AJ, von Knobelsdorff-Brenkenhoff F, Wallis W, Korvink JG, Bissell MM, Schulz-Menger J, and Markl M. 4D flow magnetic resonance imaging in bicuspid aortic valve disease demonstrates altered distribution of aortic blood flow helicity. Magn Reson Med 2013; 71(4):1542-53. [PMID: 23716466]
  16. Kowalski WJ, Dur O, Wang Y, Patrick MJ, Tinney JP, Keller BB, and Pekkan K. Critical transitions in early embryonic aortic arch patterning and hemodynamics. PLoS ONE 2013; 8(3):e60271. [PMID: 23555940]
  17. Talkhabi M, Aghdami N, and Baharvand H. Human cardiomyocyte generation from pluripotent stem cells: A state-of-art. Life Sci. 2015; 145:98-113. [PMID: 26682938]
  18. Batalov I, and Feinberg AW. Differentiation of Cardiomyocytes from Human Pluripotent Stem Cells Using Monolayer Culture. Biomark Insights 2015; 10(Suppl 1):71-6. [PMID: 26052225]
  19. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, and Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131(5):861-72. [PMID: 18035408]