CHAPTER 8: MOLECULAR AND CELLULAR DEVELOPMENT OF THE HEART

INTRODUCTION

Cardiac development is a fascinating journey that starts early in embryonic development and brings cells from a homogeneous pluripotent state to a highly specialized array of differentiated tissues organized in a complex functional architecture. Heart development has been addressed extensively in monographic texts,^1,2 and here we will focus in summarizing the aspects more relevant to understand its origin, morphogenesis, and physiology. The heart is the first functional organ in the mammalian embryo; however, its full development spans the whole intrauterine period and is finished only in the postnatal period. Therefore, most of the complex morphogenetic events and the cell proliferation, migration, and differentiation processes involved in heart formation take place in the context of a beating heart that provides the circulatory function essential for embryonic, fetal, and postnatal development. Cardiac malformations are the most frequent congenital malformations in humans (around 1%), which correlates with the complexity of generating a four-chambered heart from an initially linear cardiac tube. Although genetic determinants of cardiac malformation are increasingly being discovered, the precise understanding of how specific developmental defects lead to a malformed newborn heart is still a difficult task and will likely demand the development of systems biology approaches capable of modeling cardiac development in a predictive manner. Importantly, during development, cardiomyocytes proliferate extensively. However, this ability is limited in the adult heart and so is cardiac regenerative capacity. The molecular and cellular pathways involved in cardiac development, therefore, have become a paradigm for the design of cardiac regenerative strategies in the adult heart.^3,4 In this chapter, we will address the main aspects of cardiac embryonic development, including the origin of cardiac precursors, the formation of the cardiac crescent, the morphogenesis of the primary heart tube, and the recruitment of additional lineages from the epicardium and the neural crest. We will also discuss the progressive incorporation of second heart field precursors and the differentiation of the different cardiomyocyte subtypes. In addition, we will present current knowledge on the morphogenesis of cardiac chambers, septa, and valves. Finally, we will review the knowledge on cardiomyocyte proliferation, differentiation, and hypertrophy and how the surrounding signaling and cellular environment influences these processes. Our knowledge of cardiac development mainly derives from studies in animal models in which experimental embryology and genetic engineering is accessible. We will describe human cardiac development,⁵ although the knowledge presented here on the mechanisms involved derives from experimental animal models, mainly mouse and chicken, which represent the genetic and embryological models closest to humans.

CARDIAC EMBRYOGENESIS

Allocation and Specification of Cardiac Progenitors during Gastrulation

Cardiac precursors are found shortly after gastrulation (the formation of the three embryonic layers: ectoderm, endoderm, mesoderm) within the mesodermal component of the splanchnopleural layer of the anteriormost lateral plate (Fig. 8–1).^2,6,7 This area is called the cardiogenic area and is formed by early gastrulating embryonic mesoderm. ...