Abstract
Simple SummaryIn adult mammals, including humans, new blood vessels are formed mostly via a process named sprouting angiogenesis. In physiological conditions, angiogenesis can improve blood perfusion and oxygen supply of organs and tissues, but it can also be harmful. For example, active angiogenesis promotes tumor growth. To be able to regulate angiogenesis, it is necessary to understand the underlying molecular and cellular mechanisms, and this, in turn, requires the development of suitable models. Here we review the existing models of sprouting angiogenesis and describe an in vitro approach that is suitable for further deciphering its cellular and molecular mechanisms, preclinical drug testing, and research in regenerative medicine under conditions close to the in vivo conditions. This approach is based on the use of 3D tissue aggregates named spheroids and consisting of endothelial cells lining the inner surface of blood vessels, one or more other types of cells forming the vessel wall, and the extracellular matrix. It has a great potential for further refinement for use in such applications as formation of prevascularized tissues for bioprinting and tissue engineering.Sprouting angiogenesis is the common response of live tissues to physiological and pathological angiogenic stimuli. Its accurate evaluation is of utmost importance for basic research and practical medicine and pharmacology and requires adequate experimental models. A variety of assays for angiogenesis were developed, none of them perfect. In vitro approaches are generally less physiologically relevant due to the omission of essential components regulating the process. However, only in vitro models can be entirely non-xenogeneic. The limitations of the in vitro angiogenesis assays can be partially overcome using 3D models mimicking tissue O2 and nutrient gradients, the influence of the extracellular matrix (ECM), and enabling cell-cell interactions. Here we present a review of the existing models of sprouting angiogenesis that are based on the use of endothelial cells (ECs) co-cultured with perivascular or other stromal cells. This approach provides an excellent in vitro platform for further decoding of the cellular and molecular mechanisms of sprouting angiogenesis under conditions close to the in vivo conditions, as well as for preclinical drug testing and preclinical research in tissue engineering and regenerative medicine.
Highlights
Development of the experimental models for tissue vascularization research was substantially accelerated in early 1960s after Folkman et al [1,2] demonstrated that the growth of a tumor depends on how well it is vascularized
It was shown that endothelial cells (ECs) that are co-cultured with adhesive perivascular cells such as vascular smooth muscle cells (VSMCs), pericytes, fibroblasts, MSCs, and osteoblasts in heterotypic tissue spheroids, demonstrate a very specific localization pattern where they form a monolayer at the spheroid surface and a primitive 3D capillary bed-like network within the spheroid core [66,67,68] (Figures 1B and 2 show our own unpublished data [69])
In the majority of studies, the ECs/perivascular cells ratio of 1:1 is considered as an optimal ratio [73,74,75], in a rather early study it was shown that tissue spheroids that contained up to 10 % of ECs developed dense endothelial networks, while the use of higher percentages of ECs led to less elongated structures that were similar to cell clumps [66]
Summary
Development of the experimental models for tissue vascularization research was substantially accelerated in early 1960s after Folkman et al [1,2] demonstrated that the growth of a tumor depends on how well it is vascularized. Vasculogenesis is the de novo generation of a primitive vascular network via mesoderm-derived endothelial precursors (angioblasts) migration, differentiation, and alignment into vascular tubes (reviewed in [9]) This process primarily occurs during embryonic development. We present a review of the existing models of sprouting angiogenesis that are based on the use of heterotypic spheroids comprising of Ecs and other types of cells. We maintain that this approach provides an excellent in vitro platform for further deciphering of the cellular and molecular mechanisms of sprouting angiogenesis under conditions that are close to the in vivo conditions, as well as for preclinical drug testing and preclinical research in tissue engineering and regenerative medicine
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