Vascular organoids: unveiling advantages, applications, challenges, and disease modelling strategies

Abstract

Understanding mechanisms and manifestations of cardiovascular risk factors, including diabetes, on vascular cells such as endothelial cells, pericytes, and vascular smooth muscle cells, remains elusive partly due to the lack of appropriate disease models. Therefore, here we explore different aspects for the development of advanced 3D in vitro disease models that recapitulate human blood vessel complications using patient-derived induced pluripotent stem cells, which retain the epigenetic, transcriptomic, and metabolic memory of their patient-of-origin. In this review, we highlight the superiority of 3D blood vessel organoids over conventional 2D cell culture systems for vascular research. We outline the key benefits of vascular organoids in both health and disease contexts and discuss the current challenges associated with organoid technology, providing potential solutions. Furthermore, we discuss the diverse applications of vascular organoids and emphasize the importance of incorporating all relevant cellular components in a 3D model to accurately recapitulate vascular pathophysiology. As a specific example, we present a comprehensive overview of diabetic vasculopathy, demonstrating how the interplay of different vascular cell types is critical for the successful modelling of complex disease processes in vitro. Finally, we propose a strategy for creating an organ-specific diabetic vasculopathy model, serving as a valuable template for modelling other types of vascular complications in cardiovascular diseases by incorporating disease-specific stressors and organotypic modifications.

Keywords: Angiopathy; Microvascular and macrovascular complications; Organ-specific endothelial dysfunction; Pluripotent stem cells; Vascular disease modelling; Vasculopathy.

Fig. 1

Advantages of Human iPSCs-Derived 3D Vascular Organoids Over Conventional 2D Models. A comparison between 2D (left) and 3D (right) systems highlights the advantages of human iPSCs-derived 3D vascular organoids. These patient-derived organoids closely resemble native blood vessels, containing crucial vascular cell types such as mural and endothelial cells, thus enabling better mimicry of native pathophysiological responses. Their personalized nature offers the potential for studying individualized drug responses, as hiPSCs-derived organoids retain patient-specific metabolic and hyperglycaemic memory from the original tissue/organ. These functional vascular organoids can be integrated with other organoids or engineered tissue constructs. The absence of irrelevant cells in the microenvironment and inclusion of all major vascular cell types streamline downstream experimental analyses. However, the simplified tissue complexity may be considered a limitation in constructing fully organotypic blood vessels

Fig. 2

Potential Applications of Human Vascular Organoids. Human vascular organoids offer a wide range of potential applications, encompassing various fields such as basic biological and developmental science, disease modelling, drug screening, and regenerative medicine. These versatile organoids have the capacity to contribute to diverse research areas and hold promise for advancing our understanding of vascular biology and facilitating the development of novel therapeutic strategies

Fig. 3

Importance of Interaction between Mural Cells and Endothelial Cells in Vascular Health. This figure highlights the significance of the interaction between mural cells and endothelial cells in ensuring proper blood vessel function. (1) Direct physical contact between mural cells and endothelial cells plays a crucial role in maintaining vascular integrity. (2) Both cell types communicate through the secretion of paracrine factors, further supporting the functional coordination of the blood vessel. (3) The extracellular matrix (ECM) also influences the behaviour and function of both cell types. Disruption of these intimate interactions can lead to the development of vascular diseases. Moreover, impairments affecting one cell type in vascular disease can have consequential effects on the other cell type. Mural cells exert a multifaceted impact on endothelial cells (ECs), regulating vasoconstriction and vasodilation, preserving vascular integrity and function, aiding vessel development and stabilization, and contributing to extracellular matrix (ECM) production for vasculature patterning. ECs, in turn, play crucial roles in lumen formation, secretion of vasoprotective factors, interaction with immune cells, and autocrine signalling. They also control mural cell recruitment, proliferation, migration, and specialization

Fig. 4

Utilizing Patient-Derived Induced Pluripotent Stem Cells (iPSCs) for In Vitro Disease Modelling of Vascular Complications. The figure showcases the application of patient-derived iPSCs in the in vitro modelling of vascular complications. (1) Patient-derived iPSCs are differentiated into blood vessel organoids comprising all vascular cell types. CRISPR-Cas9 technology allows the generation of isogenic iPSC control lines by repairing mutations or introducing patient-specific gene editions or other genes of interest. (2) By comparing these intact blood vessels from individuals with vascular diseases to healthy controls, researchers can identify the cellular and molecular mechanisms underlying the disease phenotype. (3) These vascular organoids serve as valuable tools for in vitro disease modelling of specific vascular complications and can be utilized in high-throughput drug screening to discover novel therapeutic agents, facilitating pre-clinical and/or clinical trials

Fig. 5

A Strategy for In Vitro Modelling of Vascular Complications: Focus on Diabetic Vasculopathy/Angiopathy. The right panel highlights the requirement of four different cell types for comprehensive modelling of vascular complications. The blue texts (A–D) indicate how each cellular and environmental element is incorporated to generate an intact organoid model of diabetic vasculopathy/angiopathy, elucidating the mechanisms underlying abnormal vascular cell behaviours (pink box). A illustrates the generation of blood vessel organoids from patient-derived induced pluripotent stem cells (iPSCs), enabling the study of mural cell transformation, endothelial mesenchymal transition (EndoMT), and genetic modifications. Also, microfluidic technology allows the introduction of different flow types and facilitates the formation of perfused blood vessel organoids. B demonstrates the simulation of environmental stressors by adding pathological risk factors to the culture media. C shows the incorporation of immune cells in a co-culture fashion or through the addition of pro-inflammatory cytokines. D addresses the ongoing challenge of including organ-specific cell types in the model to induce organ-specific vascular phenotype. EndoMT; endothelial mesenchymal transition