Organ-on-the-vascular-network
Artificial vessels, individually tuned to a specific organ
Maria Tolmacheva, XX2 century
A group of researchers has developed a method for producing functioning human blood vessels and demonstrated that these vessels can carry blood and feed it to model organs and tumors grown in the laboratory. The method described in a paper published on September 9 in Nature (Palikuqi et al., Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis) is based on a recently discovered protein capable of rejuvenating vascular endothelial cells, returning them to a plastic state in which they easily grow and adapt to surrounding tissues.
The accuracy of modeling human diseases on animals leaves much to be desired. This complicates the development of therapeutic agents and methods for restoring damaged organs or replacing them with artificially grown ones. At the same time, there are always not enough donor organs. And sometimes transplanted organs fail due to poor blood supply. In addition, both organs and tumors are different – and the vessels in them are also different and work differently. Therefore, success in restoring and growing organs, as well as in targeting therapy for a specific type of tumor, depends on how well we understand exactly what properties artificial vessels should have, and how well we can "tune" them so that they are similar in properties to the real ones and can work correctly in a particular organ.
Currently used models of the "organ-on-a-chip" type consist, as a rule, of microcontainers and microchannels: cell cultures of an organ or tumor are placed in containers, fluids necessary for their functioning are supplied and diverted through channels. Microchannels in this case may well be lined with endothelial cells and to some extent mimic blood vessels. But such devices have many limitations: extremely small volume, lack of cellular freedom, separation of endothelial cells from parenchymal (the main functional cells of organs) or tumor with semipermeable materials, etc. Within the framework of this technology, vessels do not have the opportunity to develop and adapt to other types of tissues.
The current study is based on the discovery of the first author of the paper, Dr. Brisa Palikuqi from the University of California at San Francisco (University of California, San Francisco). She found out that a protein called ETV2 is able to significantly change the properties of adult vascular cells grown in culture. ETV2 is an "innovative transcription factor" capable of reprogramming cells by turning on or off a wide set of genes.
"Mature endothelial cells cannot form new blood vessels from scratch," says Palikuki. – Our idea was to use ETV2 to return endothelial cells to a young state in which they can form new vessels based on signals coming from surrounding tissues. Thus, they are embedded in the surrounding tissues and trained to perform specialized functions. We also found that a mixture of three tissue-forming "matrix" proteins helped rejuvenated endothelial cells (R-VEC) to form vessels in devices operating with bodily fluids, in particular, blood. We got a three-dimensional platform, we called it "Organ-on-vascular-network". We can use R-VEC to create tissue-specific blood vessels that can help in the regeneration of various organs."
The new vessels easily adapted to the circulatory system of mice and remained viable for several months. Also, R-VEC vessels supported the growth of laboratory healthy or cancerous organoids (organs grown in artificial conditions). R-VEC opens up broad prospects for regenerative medicine and cancer control. Now it is possible to create models with fabrics well equipped with vessels. This will make it possible to accurately simulate human diseases and will save researchers from having to resort to animal models.
To demonstrate the versatility of the developed technology, the team showed that in laboratory conditions R-VEC are able to provide blood vessels (vascularize) and maintain the functionality of clusters of human islet cells – islets of Langrenance, which produce insulin in the pancreas and are damaged by an autoimmune response in type 1 diabetes mellitus. Islets are sometimes transplanted during diabetes treatment, but if they are transplanted into easily accessible places, such as the skin, they cannot develop a reliable vascular system there. Therefore, they have to be transplanted into the liver, and this makes it difficult to monitor the transplant.
"The ability of R-VEC to vascularize human islets of Langrenance will lay the foundation for the creation of long–lasting islets for the potential treatment of type I diabetes," explains co-author of the article Dr. Joe Zhou (Joe Zhou). – Such vascularized islets would be more accessible, would have a better survival rate and would be superior to the treatment methods available within the existing technologies today. They would also open up new possibilities for testing drugs aimed at stopping the autoimmune reaction."
Clusters of human pancreatic islet tissue (red) with an integrated network of blood vessels (green) in a Petri dish.
R-VEC vascular networks are already being used to study human diseases. "We use the R-VEC vascular network to study exactly how the SARS-CoV-2 virus damages small blood vessels inside organs. This creates conditions for the development of new treatments," said Dr. Robert Schwartz, associate professor of gastroenterology at Weill Cornell Medicine.
"A new frontier in regenerative medicine is opening up, as some of the main obstacles facing this industry will now be overcome," added Dr. Shahin Rafii, professor of medical genetics and head of the Department of regenerative medicine at Weill Cornell Medicine.
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