The cardiovascular system is comprised of a complex network of vessels connecting the heart with diverse organs and tissues to maintain their homeostasis in response to physiological and pathological changes. Many diseases are related to cardiovascular defects, such as excessive blood vessel formation (for example, angiogenesis in cancer) or impaired blood vessel functioning (for example, atherosclerosis and stroke).
Reliable, predictive and high throughput cell-based models for screening of blood vessel-targeting drugs are key to the efficient discovery and development of novel treatments targeting the cardiovascular system. Functional applications based on human induced pluripotent stem cell (hiPSC)-derived cells of the cardiovascular system are promising candidates to fulfil these requirements. Previously, Ncardia scientists have developed protocols for large-scale manufacturing of human iPSC-derived endothelial cells. One of our aims now, together with collaborators at Mimetas and LUMC (Prof. A.J. van Zonneveld and Dr. V. van Duinen), is to integrate these cells into a state-of-the-art assay systems for phenotypic screening of candidate drugs targeting the formation of new blood vessels.
We have shown that upon triggering with proangiogenic factors the cells form an intricate capillary network in a 3-dimensional matrix comprising tip cells, stalk cells and a clear vascular lumen. Current activities are aimed at further validating the assay using a set of angiogenesis modulators and to set up a high throughput-compatible approach for quantification. Altogether, the current collaborative project holds promise for future high throughput screening of blood vessel-targeting drugs in a predictive, translational and robust assay representing the complex three-dimensional structure which is typical for a functional capillary network.
The ﬁgure shows a schematic representation of one angiogenesis compartment comprising three interconnected microﬂuidic channels. hiPSC-ECs are cultured in the upper channel, proangiogenic factors are added to the lower channel and the middle channel comprises a 3-dimensional matrix. Upon formation of a gradient of proangiogenic factors, new capillaries are sprouting from the upper channel into the matrix, ultimately forming a capillary lumen. VE-cadherin is in green, F-actin is in red, nuclei are in blue.