Identification of a hybrid myocardial zone in the mammalian heart after birth

Abstract

Noncompaction cardiomyopathy is characterized by the presence of extensive trabeculations, which could lead to heart failure and malignant arrhythmias. How trabeculations resolve to form compact myocardium is poorly understood. Elucidation of this process is critical to understanding the pathophysiology of noncompaction disease. Here we use genetic lineage tracing to mark the Nppa+ or Hey2+ cardiomyocytes as trabecular and compact components of the ventricular wall. We find that Nppa+ and Hey2+ cardiomyocytes, respectively, from the endocardial and epicardial zones of the ventricular wall postnatally. Interposed between these two postnatal layers is a hybrid zone, which is composed of cells derived from both the Nppa+ and Hey2+ populations. Inhibition of the fetal Hey2+ cell contribution to the hybrid zone results in persistence of excessive trabeculations in postnatal heart. Our findings indicate that the expansion of Hey2+ fetal compact component, and its contribution to the hybrid myocardial zone, are essential for normal formation of the ventricular walls.

Defects in Trabecular Development Contribute to Left Ventricular Noncompaction

“…Indeed, a balance between proliferation and differentiation is critical to both generate a sufficient number of cells and initiate lineage specification [22]. The trabecular zone is characterized by the expression of the genes Irx3, Cx40, Nppa, Etv1, Bmp10, Slit2 and Sema3a whereas the compact zone is characterized by the expression of Tbx20, Hey2, Loxl2 and N-Myc [6,[22][23][24][25][26][27][28] (Fig. 1A).…”

“…The process of compaction is poorly described in the literature and often causes confusion. Certain authors support a dynamic coalescence of ventricular trabeculae, while others argue in favor of a remodeling of the compact zone that undergoes an extensive proliferation resulting in the zipping-up of trabeculae [24]. Interestingly, recent genetic tracing and retrospective clonal analysis in the mouse has suggested that the compaction step may be in part driven by expansion of the fetal compact myocardium into the trabecular layer through its higher proliferative activity.…”

“…Interestingly, recent genetic tracing and retrospective clonal analysis in the mouse has suggested that the compaction step may be in part driven by expansion of the fetal compact myocardium into the trabecular layer through its higher proliferative activity. This leads to the formation of a hybrid zone composed of cardiomyocytes derived from both the compact and trabecular zones [24]. Preventing proliferation of cardiomyocytes in the compact zone compromises the formation of the hybrid zone, and results in a thin and non-compacted ventricular myocardium with persistent trabeculae associated with contraction defects.…”

“…However, recent evidence indicates that excessive trabeculation results from defective compaction zone expansion and not from failure of the compaction of pre-existing trabeculae [2,55]. Inhibiting proliferation of the compact zone by deleting Yap1, a key transcription co-factor required for normal cardiomyocyte proliferation, prevents the expansion of the compact zone and results in noncompaction of the ventricular myocardium [24]. Several other mouse models including the ventricular Nkx2-5-conditional deletion support this assumption; however, most of these mutants present a very thin compact layer and are embryonic lethal and thus do not fully recapitulate symptomatic features observed in LVNC patients.…”

Mechanisms of Trabecular Formation and Specification During Cardiogenesis

“…Whether Nrg1/ErbB2/4 regulate cardiomyocytes polarity to control their entry into myocardium in the mouse is unknown. With the genetic tools such as, Hey2 CreERT2 , which is specifically active in compact zone at early embryonic stage, and Nppa CreERT2 , which is specifically active in trabecular cardiomyocytes 68 , to separate trabecular and compact cells being available, more definitive experiments can be designed to reveal the mechanisms of trabeculation and compaction in the future.…”