The endocardial cushions are one of the most important transient embryonic structures in the developing heart. They serve as the primary building blocks for atrioventricular (AV) septation, valve formation, and outflow tract remodeling. Despite their temporary nature, endocardial cushions have a permanent influence on the architecture and function of the heart, as they ultimately give rise to critical cardiac components such as the atrioventricular septa, valves, and membranous interventricular septum.
This post explores the formation of endocardial cushions in detail, including their origin, cellular contributions, molecular regulation, morphogenetic events, and clinical implications.
1. Introduction
The formation of endocardial cushions is a pivotal event in cardiac morphogenesis, taking place during the 4th and 5th weeks of human embryonic development. The process begins with the accumulation of extracellular matrix (ECM) between the endocardium and myocardium, a substance known as cardiac jelly, within the atrioventricular (AV) canal and outflow tract.
Once formed, the cushions act as morphogenetic primordia that will later fuse, remodel, and transform into the atrioventricular septa and valves, as well as contribute to outflow tract septation. Any disruption of this process can result in severe congenital malformations such as atrioventricular septal defects (AVSD), persistent truncus arteriosus, or valvular stenosis/regurgitation.
2. Embryonic Context
Before endocardial cushion formation, the heart exists as a linear heart tube consisting of:
- Sinus venosus
- Primitive atrium
- Primitive ventricle
- Bulbus cordis
- Truncus arteriosus
As the heart undergoes looping (days 23–28), the AV canal is positioned centrally, and it becomes a crucial site where endocardial cushion development is initiated.
2.1 Cardiac Jelly Deposition
Cardiac jelly is a specialized ECM-rich layer secreted by the myocardium and located between the endocardium (inner lining) and myocardium (outer muscle layer). It consists of:
- Hyaluronic acid
- Glycoproteins
- Proteoglycans
- Collagen fibers
This jelly serves as a scaffold for cell migration and cushion formation.
3. Initiation of Endocardial Cushions
3.1 Regional Swelling
At approximately week 4 of gestation, cardiac jelly within the AV canal and outflow tract begins to swell at specific sites, forming localized thickenings known as the superior (dorsal) and inferior (ventral) endocardial cushions. Additional lateral cushions form slightly later.
3.2 Endocardial-to-Mesenchymal Transformation (EMT)
One of the most important steps is the transformation of endocardial cells into mesenchymal cells:
- Endocardial cells overlying the cushions receive myocardial signals (e.g., BMP2, TGF-β, Notch)
- They lose their tight junctions, detach, and invade the cardiac jelly
- This process is known as endocardial EMT
- The result is a population of mesenchymal cells that populate the cushions, giving them a cellular, proliferative, and migratory character
4. Growth and Remodeling of Cushions
4.1 Cellular Contribution
Cushions are populated not only by EMT-derived mesenchyme but also by:
- Cardiac neural crest cells (especially in outflow tract cushions)
- Epicardial-derived cells (EPDCs) in later stages
- Endothelial progenitors that migrate into the ECM
4.2 Fusion of Cushions
The superior and inferior cushions grow toward each other and fuse in the midline by the end of the 5th week. This fusion divides the single AV canal into right and left AV orifices, thereby aligning the atria with their respective ventricles.
5. Morphogenetic Roles of Endocardial Cushions
5.1 Formation of AV Septa
Cushion fusion contributes to the atrioventricular septum, which separates the right and left AV canals. This is essential for:
- Proper alignment of atria and ventricles
- Prevention of blood mixing
- Establishing a pathway for future valve development
5.2 Contribution to Interventricular Septum
The membranous interventricular septum forms partly from cushion tissue. This is critical because defects in cushion formation can lead to membranous ventricular septal defects (VSDs), one of the most common congenital heart malformations.
5.3 Valve Formation
Endocardial cushions give rise to:
- Mitral and tricuspid valve leaflets
- Chordae tendineae and papillary muscles (through remodeling)
- Semilunar valves (in the outflow tract cushions)
Valve formation involves cushion elongation, thinning, and sculpting into leaflet-like structures that will later support unidirectional blood flow.
6. Molecular Regulation
6.1 Key Signaling Pathways
Several molecular pathways regulate cushion formation:
- BMP2 (Bone Morphogenetic Protein 2): Induces EMT in endocardial cells
- TGF-β (Transforming Growth Factor-beta): Drives mesenchymal cell proliferation and ECM production
- Notch signaling: Maintains endocardial cell plasticity, enabling EMT
- VEGF (Vascular Endothelial Growth Factor): Balances EMT; too much inhibits mesenchymal transformation
- Wnt/β-catenin signaling: Promotes cushion cell proliferation
6.2 Transcription Factors
- GATA4, TBX2, TBX20: Control cushion positioning and growth
- SOX9: Promotes mesenchymal differentiation
- NFATc1: Maintains endocardial identity before EMT
7. Outflow Tract Cushions
While the AV cushions are crucial for canal partitioning, outflow tract (conotruncal) cushions are equally important for separating systemic and pulmonary circulation. These cushions:
- Arise partly from neural crest-derived mesenchyme
- Fuse to form the aorticopulmonary septum
- Divide the truncus arteriosus into aorta and pulmonary trunk
Defects here lead to conotruncal anomalies such as tetralogy of Fallot or persistent truncus arteriosus.
8. Hemodynamic Forces and Cushion Maturation
Blood flow through the heart exerts shear stress and pressure, which are crucial for:
- Proper cushion growth
- Remodeling into thin valve leaflets
- Alignment of AV canal with ventricles
Abnormal flow patterns (e.g., in embryonic heart defects) can lead to hypoplastic cushions or misaligned valves.
9. Clinical Significance
9.1 Atrioventricular Septal Defects (AVSD)
Failure of cushion fusion causes complete AV canal defect with:
- Common AV valve
- Incomplete separation of right and left AV orifices
- Often seen in Down syndrome (trisomy 21)
9.2 Valvular Defects
Abnormal cushion remodeling leads to:
- Mitral or tricuspid atresia
- Bicuspid aortic valve (if outflow tract cushions are affected)
- Congenital valve stenosis or regurgitation
9.3 Ventricular Septal Defects
Membranous VSDs occur if the cushion contribution to the interventricular septum fails.
10. Diagnostic and Research Perspectives
- Fetal echocardiography can visualize AV canal and cushion swelling
- 3D ultrasound and MRI are emerging tools for detailed fetal heart imaging
- Animal models (mouse, chick, zebrafish) are used to study cushion morphogenesis and gene function
11. Experimental Insights
Genetic knockout studies in mice have shown:
- BMP2 or TGF-β2 deficiency leads to absent cushions
- Notch1 knockout causes severe endocardial defects
- Neural crest ablation disrupts outflow tract cushion fusion, causing conotruncal malformations
These models underline the multifactorial control of cushion formation.
12. Summary Table
| Stage | Event | Key Regulators |
|---|---|---|
| Week 4 | Cardiac jelly deposition | Myocardial signaling |
| Week 4–5 | Endocardial EMT | BMP2, TGF-β, Notch |
| Week 5 | Cushion cellularization | Mesenchymal proliferation |
| Week 5–6 | Cushion fusion | Mechanical forces, ECM remodeling |
| Week 6–8 | Valve sculpting | Wnt, VEGF, Sox9 |
| Week 7–8 | Septation complete | AV septum formed |
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