Unraveling Endothelial Cell Migration: Insights into Fundamental Forces, Inflammation, Biomaterial Applications, and Tissue Regeneration Strategies

Abstract

Cell migration is vital for many fundamental biological processes and human pathologies throughout our life. Dynamic molecular changes in the tissue microenvironment determine modifications of cell movement, which can be reflected either individually or collectively. Endothelial cell (EC) migratory adaptation occurs during several events and phenomena, such as endothelial injury, vasculogenesis, and angiogenesis, under both normal and highly inflammatory conditions. Several advantageous processes can be supported by biomaterials. Endothelial cells are used in combination with various types of biomaterials to design scaffolds promoting the formation of mature blood vessels within tissue engineered structures. Appropriate selection, in terms of scaffolding properties, can promote desirable cell behavior to varying degrees. An increasing amount of research could lead to the creation of the perfect biomaterial for regenerative medicine applications. In this review, we summarize the state of knowledge regarding the possible systems by which inflammation may influence endothelial cell migration. We also describe the fundamental forces governing cell motility with a specific focus on ECs. Additionally, we discuss the biomaterials used for EC culture, which serve to enhance the proliferative, proangiogenic, and promigratory potential of cells. Moreover, we introduce the mechanisms of cell movement and highlight the significance of understanding these mechanisms in the context of designing scaffolds that promote tissue regeneration.

Keywords: angiogenesis; biomaterials; cell migration; endothelial cells; inflammation.

Figure 1

Collective migration of epithelial cells. Leader cells begin migration, whereas follower cells trail behind them. Cadherin stable junctions connect cells and allow them to migrate with the lamellipodia. Owing to strong focal adhesions, each cell makes an equal contribution in migration (designed with BioRender: https://biorender.com/).

Figure 2

Six crucial steps of endothelial cell migration. (1) Filopodia detection of motile stimuli. (2) Cellular extension of protruding lamellipodium. (3) Attachment of the protrusions to the ECM. (4) Stress fiber-mediated contraction and translocation of the cell. (5) Rear release of the cell edge. (6) Recycling of membrane receptors from the cell’s rear to its front (designed with BioRender: https://biorender.com/).

Figure 3

Hypoxia and inflammation in the progression of pathological angiogenesis. VEGF is the main factor contributing to the induction and progression of angiogenesis. In pathological microenvironments, such as cancer, VEGF is overproduced due to processes triggered by the lack of oxygen and immune/inflammatory responses. Accumulation of cytokines modulates the polarization of macrophages to an M2-like phenotype, which is important in promoting tumor progression and invasion. The key regulator involved in M2 activation is TGF-β, which is further released, i.e., from that macrophage and involved in the upregulation of VEGF expression. Then, overstimulated ECs begin to migrate and proliferate excessively resulting in the expansion of new blood vessels supporting tumor growth (designed with BioRender: https://biorender.com/).

Figure 4

Impact of substrate stiffness on cellular phenotype. Substrate stiffness has been found to influence cell stress fibers as well as focal adhesions in different cell categories. Cell function is constantly modulated by the mechanical surroundings through cytoskeletal alterations and actomyosin retractility (designed with BioRender: https://biorender.com/).