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Heart Regeneration using Cardiac Stem Cells: Lessons from Embryonic Development

  1. Introduction

Congenital heart defects (CHDs) are usually apparent at birth and are characterised by structural abnormalities, such as atrial or ventricular septation defects, electrical conduction abnormalities or cardiomyopathies. One of the primary causes of cardiomyopathy is the loss and/or damage of cardiomyocytes (CM). In order to replenish the lost/damaged cells, an appropriate source is needed as a cell-replacement therapeutic approach. An attractive candidate is cardiac progenitor cells (CPCs), which could be driven to give rise to CMs. However, our understanding of CPCs and how to obtain a pure and effective CM population for the clinical setting remains limited. By devising methods to distinguish between distinct early CPC populations and following their subsequent differentiation we will better understand the pathophysiology of CHDs.

During development, the CM lineage is highly specialised, comprising of CPCs allocated in a discrete and temporal order (Evans et al., 2010). At embryonic day (E) 7.5 in mice (Rana et al., 2013; Downs and Davies, 1993), the heart tube is the prime structure that will eventually give rise to the heart proper. It is populated by two distinct sets of CPCs derived from two anatomical regions; the first heart field (FHF, also known as the cardiac crescent) which will give rise to the left ventricle (LV) and parts of the atria, and the second heart field (SHF) that contributes towards the right ventricle, outflow tract and the remaining parts of the atria, including the septum (Rana et al., 2013; Downs and Davies, 1993; Tam et al., 1997; Buckingham et al., 2005). These fields are genetically distinguishable, at E7.5, by expression of specific transcription factors (TF) (Rana et al., 2013; Prall et al., 2007; Ma et al., 2008).

CHDs are often linked to transcriptional networks that orchestrate heart development. Tbx5, the T-box TF haploinsufficient in Holt-Oram syndrome, is one of the cardinal TFs essential for cardiac development (Bruneau et al., 1999). Its expression is also of paramount importance for obtaining CMs from embryonic stem cells (ESC), human induced pluripotent stem cells (hiPSC), or via direct reprogramming of any cell type (Wada et al., 2013; Fu et al., 2013; Christoforou et al., 2013b; Christoforou et al., 2013a; Zhou et al., 2012; Song et al., 2012; Qian et al., 2012; Nsair et al., 2012; Chen et al., 2012). Recent experiments performed in the adult zebrafish, reported re-expression of tbx5 (among other cardinal TFs) on ventricular ablation leading to complete heart regeneration (Zhang et al., 2013). Thus, the Tbx5 transcriptional network is important not only for initiating early cardiac specification, but also to prime the regenerative mechanism in adult lower vertebrates. The importance of this TF in mammalian heart regeneration has not been examined in detail, primarily because of the lack of specific molecular markers able to distinguish between CPC progenies…

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