Optimizing the Univentricular Heart: the Potentials of Mesenchymal Stromal Cell Therapy for patients with Hypoplastic Left Heart Syndrome

Abstract

Hypoplastic left heart syndrome is a congenital heart disease in which the left side of the heart is highly underdeveloped, hindering left-sided systemic circulation after birth. The condition is rare and accounts for only 9% of all congenital heart diseases but is fatal when left untreated. A three-stage univentricular palliative intervention, in which the right ventricle is tuned to sustain systemic circulation, has changed the prognosis of this condition. However, this univentricular circulation cannot be maintained indefinitely, as the right ventricle physiologically is not built to drive systemic circulation, which often leads to cardiovascular complications such as heart failure and, subsequently, complications such as arrhythmias. Potentially, (stem) cell-based therapies could enhance proper ventricular function to a state more suitable for systemic circulation. This review will discuss the potential therapeutic role of mesenchymal stromal cells in patients with hypoplastic left heart syndrome. The morphological differences between the left and right ventricles are significant and must be considered when designing treatments for right ventricle dysfunction. Thus, the intrinsic differences between the two ventricles and the subsequent cellular mechanisms involved in this pathophysiological condition will be a topic of interest in the first part of this review. The paradigm of how mesenchymal stromal cells act in the injured myocardium has been shifted from a mechanism based on cellular engraftment and differentiation towards the cardiac lineage to one primarily based on the paracrine effect. Several preclinical studies will be discussed, including the different disease models for hypoplastic left heart syndrome that laid the groundwork for clinical application. Based on recent literature, we will shed light on the mesenchymal stromal cell secretome setting up cellular pathways that could cause the elucidated therapeutic effect, highlighting reducing reactive oxygen species (-mediated damages) in the myocardium involved in the right ventricular failure. The timing and route of administration are important factors in the effectiveness of therapy and will also be reviewed here. We will conclude with our view on these stem cell-based therapies' most effective application strategies. This review will thus provide an overview of the various ways mesenchymal stromal cells can be a valuable cell source for infants suffering from hypoplastic left heart syndrome to affect right ventricle dysfunction and improve longevity and quality of life.