Research Project of Soft Tissue Engineering and Mechanobiology

Manipulation of angiogenesis by using the Notch signaling pathway as an engineering tool


The vasculature transports waste, oxygen and nutrients, as the maximum distance for diffusion is only 200µm. Therefore, a functional vasculature is pivotal for regeneration of damaged tissues or the embedding of tissue engineered grafts in vivo. When there is a lack of oxygen in the body, endothelial cells of adjacent blood vessels will sprout in the direction of the oxygen gradient, providing a new vessel bed, a process called angiogenesis. During sprouting, endothelial cells adopt a tip or a stalk cell phenotype. The migratory tip emerges from the parent vessel and leads proliferating stalks cells through the tissue towards the oxygen gradient. The Notch signaling pathways plays an important role during tip/stalk cell phenotype adoption in angiogenesis.

The Notch signaling pathway is a cell-cell signaling pathway, where a sending cell presents a ligand (Dll1, -3, -4 Jagged1 and Jagged2) that can bind to the receiving cells receptor (Notch1, -2, -3 and -4), which induces cleavage of the receptor, resulting in a Notch intracellular domain that is transported to the cell nucleus and aids in the transcription of target genes. Under de influence of Vascular Endothelial Growth Factor (VEGF), Dll4 - Notch1 signaling is responsible for the differentiation in tip or stalk cells, as the cells presenting the most Dll4 induces their neighboring cells to adopt a stalk cell phenotype, while they themselves adopt a tip cell phenotype. This signaling depends on the amount of Dll4 presented to the cells and is therefore location depended.

In this project, we are investigating the possibilities of using the location of Notch signaling ligands to control the location and direction of endothelial sprouting, and thereby angiogenesis, by functionalization of cell culture surfaces. We are interested in the scope of manipulation that we can exert, and aim to design materials that can incorporate these features, keeping in mind the goal of aiding tissue engineering or inducing directed vessel growth to vasculature deprived areas in the body.


Researcher: Laura Tiemeijer.

Supervisors: Prof.dr. C.M. Sahlgren (Cecilia), prof. dr. C.V.C. Bouten (Carlijn).

Funding by Åbo Akademi, Turku, Finland.