Organs on the chip: blood vessels on the chip, which can be used for angiogenesis and anticancer drugs
Release date: 2018-02-05
Image source: Medgadget
The organs on the chip can largely simulate certain internal environments in the body, for drug testing and development, and to reduce the application of animal experiments. Recently, researchers from the University of Tokyo developed a blood vessel on the chip, which was published in the recent EBioMedicine.
This chip vascular is designed to study the angiogenesis of blood vessels and to develop drugs that target angiogenesis, thereby inhibiting angiogenesis near the tumor to inhibit cancer. Of course, it can also be used for the study of other vascular related diseases.
Angiogenesis is a special process of constructing blood vessels from pre-existing blood vessels and can therefore be used as a target for some anticancer drugs. During angiogenesis, new capillaries grow out of the original blood vessels and participate in proper vascular development. However, under pathological conditions such as cancer, abnormal angiogenesis occurs, and inhibition of angiogenesis near the tumor can alleviate the progression of the tumor, and is also a promising therapeutic strategy.
Since angiogenesis begins in endothelial cells, the innermost layer of blood vessels. Vascular endothelial growth factor A (VEGF-A) and its receptor 2 (VEGFR-2) trigger most of the mechanisms that activate and regulate angiogenesis and can also be used as targets for drug development. However, testing this angiogenic drug is a very big challenge and often requires the use of animal models.
As an effective alternative to animal models, vascular chips have become the research direction of scientists. "The biochemistry of budding angiogenesis has been well understood. What is lacking now is a good system for studying effective drugs that target angiogenesis," said Dr. Yukiko Matsunaga from the University of Tokyo. She and her colleagues have jointly developed this small chip device for in vitro experiments related to vascular production. It mimics the angiogenesis that is produced by the angiogenic blood vessels triggered by the angiogenesis factor VEGF-A.
A conceptual map of VEGF-induced angiogenesis on a chip in this study. Image source: EBioMedicine
In vertebrates, VEGF contains a total of five subtypes, VEGF-A, B, C, D and placental growth factor (PIGF). VEGF is usually secreted when the tissue is hypoxic or has growth requirements. These factors play a crucial role in the construction and maintenance of vascular and lymphatic vasculature. These factors activate the signal by activating a specific tyrosine kinase VEGF receptor (VEGF-R). VEGFR-2 is the most studied receptor in human vascular endothelial cells, which can be activated by VEGF-A, and the VEGF-A\VEGFR-2 pathway plays an important role in angiogenesis. This pathway also contains DDL4 (Delta-like protein 4) \NOTCH1 (Neurogeniclocus notch homolog protein 1) which determines the initial fate of the cell tip/stem. VEGF-A binds to VEGFR-2 on vascular endothelial cells, triggering its dimerization. This triggers activation of the intracellular kinase domain of VEGFR-2, which initiates a signaling cascade, resulting in the response cell becoming a tip cell and expressing DLL4 on its surface. DLL4 interacts with the receptor NOTCH1 on its adjacent endothelial cell surface. This activates the gamma-secretase complex, causing downstream activation of the molecular pathway, resulting in reduced sensitivity to VEGF-A and stimulating endothelial cell proliferation, and thus, the cell will switch to the fate of the stem cell. This causes new "germination" to begin to appear on the original blood vessels and grow outward.
Human microvasculature in vitro was prepared using a chip. Image source: EBioMedicine
To simulate this process and environment in an in vitro chip, the researchers placed a single blood vessel in a gel and placed it on a chip. Vascular endothelial cells were added to the gel through fine needles. When VEGF-A was added to the environment, the microscope allowed the researchers to observe that new capillaries "germinated" from the original blood vessels.
Over time, the neovascularization can be observed with a microscope. Image source: EBioMedicine
This chip is a good model for angiogenesis induced by VEGF.
To further verify the bio-relationship of the device, the researchers modified it by RNA silencing prior to making microvessels, targeting the key DLL4 gene. After 10 days, in the unmodified system, the primordial blood vessels were sharp and the neovascularization was observed in the presence of VEGF. In the modified system, the edges of the blood vessels were not clear and could not form stable blood vessels. And in the presence of VEGF, similar migration behavior occurred, and some new-like "germination" can be observed.
Knocking out DLL4 will affect the angiogenesis and stability of the blood vessels. Image source: EBioMedicine
To verify that the chip model is as good as the in vivo environment, the researchers added anti-tumor drugs sorafenib or sunitinib to the chip, all of which are inhibitors of angiogenesis. In this conceptual validation trial, the researchers observed effective inhibition of angiogenesis by both drugs.
The antitumor drug sorafenib or sunitinib was added to the chip, and inhibition of angiogenesis was observed.
Image source: EBioMedicine
The team hopes the device will provide scientists with an easy way to test new angiogenesis-inhibiting drugs without the need for animal experiments. We expect more chip organs to enable new drug testing to be performed faster, easier, and at lower cost.
Reference materials:
[1] Blood Vessel on a Chip to StudyAngiogenesis and Test Anti-Cancer Drugs
[2] A Vascular Endothelial GrowthFactor-Dependent Sprouting Angiogenesis Assay Based on an In Vitro Human BloodVessel Model for the Study of Anti-Angiogenic Drugs
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