Endothelial cells (ECs) are crucial for vascular health, regulating blood flow, nutrient exchange, and modulating immune responses and inflammation. The impairment of these processes causes the endothelial dysfunction (ED) characterized by oxidative stress, inflammation, vascular permeability, and extracellular matrix remodeling. While primary ECs have been widely used to study ED in vitro, their limitations—such as short lifespan and donor variability—pose challenges. In this context, induced iECs derived from induced pluripotent stem cells offer an innovative solution, providing an unlimited source of ECs to explore disease-specific features of ED. Recent advancements in 3D models and microfluidic systems have enhanced the physiological relevance of iEC-based models by better mimicking the vascular microenvironment. These innovations bridge the gap between understanding ED mechanisms and drug developing and screening to prevent or treat ED. This review highlights the current state of iEC technology as a model to study ED in vascular and non-vascular disorders, including diabetes, cardiovascular, and neurodegenerative diseases.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons with a phenotypic and genetic heterogeneity and elusive molecular mechanisms. With the present pilot study, we investigated different genetic mutations (C9orf72, TARDBP, and KIF5A) associated with ALS by generating induced pluripotent stem cells (iPSCs) from peripheral blood of ALS patients and healthy donors. iPSCs showed the typical morphology, expressed stem cell markers both at RNA (OCT4, SOX2, KLF4, and c-Myc) and protein (Oct4, Sox2, SSEA3, and Tra1-60) levels. Moreover, embryoid bodies expressing the three germ-layer markers and neurospheres expressing neural progenitor markers were generated. Importantly, the transcriptomic profiles of iPSCs and neurospheres were analyzed to highlight the differences between ALS patients and healthy controls. Interestingly, the differentially expressed genes (DEGs) shared across all ALS iPSCs are linked to extracellular matrix, highlighting its importance in ALS progression. In contrast, ALS neurospheres displayed widespread deficits in neuronal pathways, although these DEGs were varied among patients, reflecting the disease’s heterogeneity. Overall, we generated iPSC lines from ALS patients with diverse genetic backgrounds offering a tool for unravelling the intricate molecular landscape of ALS, paving the way for identifying key pathways implicated in pathogenesis and the disease’s phenotypic variability.