Abstract
The Notch intercellular signaling pathways play significant roles in cardiovascular development, disease, and regeneration through modulating cardiovascular cell specification, proliferation, differentiation, and morphogenesis. The dysregulation of Notch signaling leads to malfunction and maldevelopment of the cardiovascular system. Currently, most findings on Notch signaling rely on animal models and a few clinical studies, which significantly bottleneck the understanding of Notch signaling-associated human cardiovascular development and disease. Recent advances in the bioengineering systems and human pluripotent stem cell-derived cardiovascular cells pave the way to decipher the role of Notch signaling in cardiovascular-related cells (endothelial cells, cardiomyocytes, smooth muscle cells, fibroblasts, and immune cells), and intercellular crosstalk in the physiological, pathological, and regenerative context of the complex human cardiovascular system. In this review, we first summarize the significant roles of Notch signaling in individual cardiac cell types. We then cover the bioengineering systems of microfluidics, hydrogel, spheroid, and 3D bioprinting, which are currently being used for modeling and studying Notch signaling in the cardiovascular system. At last, we provide insights into ancillary supports of bioengineering systems, varied types of cardiovascular cells, and advanced characterization approaches in further refining Notch signaling in cardiovascular development, disease, and regeneration.
Highlights
Notch signaling is a pathway that stems from an evolutionary trait that regulates the fate of the cell in differentiation, proliferation, immune response, and angiogenesis
How these cells communicate with the binding of Notch-associated receptors and Jagged ligand (Jag)/Delta-like ligand (Dll) associated ligands is highly dependent upon the characteristics of the cell type in question and the cell type’s ability to send or receive certain signals
The summarized works of establishing the microfluidics, hydrogel, spheroid, and 3D bioprinting to realize a range of Notch receptor and Jag/Dll ligand bindings among the human cardiovascular cells are preliminarily explored for cardiovascular development, disease modeling, and regenerative medicine, broader and better applications of the advanced bioengineering systems with various types of cardiovascular cells (CMs, smooth muscle cells (SMCs), endothelial cells (ECs), Cardiac fibroblasts (CFs), immune cells, and human-induced pluripotent stem cells (hiPSCs) derivatives) are extensively recommended
Summary
Notch signaling is a pathway that stems from an evolutionary trait that regulates the fate of the cell in differentiation, proliferation, immune response, and angiogenesis. In order to understand how the Notch pathway regulates cardiovascular development, disease, as well as regeneration and repair after injury, the contribution of individual cell types must be considered [4]. These cell types involved in the Notch signaling pathway include endothelial cells (ECs) [5], smooth muscle cells (SMCs) [6], fibroblasts (FBs) [7], cardiomyocytes (CMs [8]), immune cells [9], and hiPSC-derived cardiovascular cells [10]. Notch signaling is essential to vascular EC stabilization and EC heterogeneity establishment, as can be seen in the Notch pathway’s role in preventing ECs from undergoing apoptosis This is apparent in rat cardiac allograft vessels where impaired Notch expression leads to endothelial dysfunction during the development of transplant arteriosclerosis (TA) [29]. The Notch pathway is integral to ensuring endothelial function and vascular development in the heart
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