Stem cell advance creates functional arterial cells

Generating fully functional arterial endothelial cells is a critical task for developing new ways to combat cardiovascular disease. Now for the first time, a research team headed up at the Morgridge Institute for Research has produced functional arterial cells with both the quality and scale to be relevant for disease modelling and clinical application. The researchers employed two pioneering technologies. First, they used single-cell RNA sequencing to identify the signalling pathways critical for arterial endothelial cell differentiation; they found about 40 genes of optimal relevance. Second, they used CRISPR-Cas9 gene editing technology to create reporter cell lines to monitor arterial differentiation in real time. The team tested the cells in a mouse model of myocardial infarction. Four weeks after injection, mice treated with this cell line had an 83% survival rate, compared with 33% for controls (PNAS doi: 10.1073/pnas.1702295114).

"The cardiovascular diseases that kill people mostly affect the arteries, and no one has been able to make those kinds of cells efficiently before," explained lead author Jue Zhang. "The key finding here is a way to make arterial endothelial cells more functional and clinically useful." The ultimate goal is to apply this cell derivation process to form functional arteries that can be used in cardiovascular surgery. In many cases of vascular disease, patients lack suitable tissue from their own bodies for use in bypass surgeries. Growing arteries from an individual patient's stem cells would be cost prohibitive and take too long to be clinically useful. "Now that we have a method to create these cells, we hope to continue the effort using a more universal donor cell line," added Zhang. The lab will focus on cells banked from a unique population of people who are genetically compatible donors for a majority of the population.

See-through heart tissue reveals complexity

A team from Imperial College London has borrowed a technique from neuroscience to turn samples of heart tissue transparent, revealing the complex networks of tiny blood vessels that supply the tissue, as well as the collagen scaffold that holds everything in place. Heart tissue is highly packed with muscle cells, blood vessels, nerves and collagen, making it hard for current laser-based imaging techniques to penetrate deep enough into samples. Instead, tissue samples are sliced into thin layers, effectively rendering a 3D structure as a series of flat slices. In this latest study, the researchers used optical clearing to image adult heart tissue in 3D. By using solvents to dissolve fats locked up in cell membranes, they reduced the density of the tissue and the amount of light scattering. The result: a sample of tissue transparent enough to read text through (Scientific Reports 7 5188).

Heart disease causes the structure of the heart to change, with more connective collagen being laid down. By taking regular biopsies of cardiac tissue and making them transparent, doctors could follow the course of disease more accurately. The approach could also be used to determine whether drugs that target this fibrosis are working. "Cardiac tissue is quite dense, using standard microscopy methods we are able to image the surface of the samples, about 20–30 µm from the surface," said first author Filippo Perbellini. "With more sophisticated methods we can achieve 50–80 µm depth but we were never able to image a whole myocardial slice. We have used an existing method for preparing samples of brain tissue, but what's new here is that we have adapted it for the heart and been able to visualize samples of around 300 µm thick."

Tiny tissue seeds produce fully functional livers

Many diseases can lead to liver failure, but significantly fewer livers are available than can meet transplant needs. To help address that shortage, researchers at MIT, Rockefeller University and Boston University have developed a new way to engineer liver tissue, by organizing tiny subunits containing three types of cells embedded into a biodegradable tissue scaffold. In a study of mice with damaged livers, the researchers found that, after being implanted in the abdomen, the tiny structures expanded 50-fold and were able to perform normal liver tissue functions. "Our goal is that one day we could use this technology to increase the number of transplants that are done for patients, which right now is very limited," said MIT's Sangeeta Bhatia. The engineered livers could also help people who suffer from chronic liver disease but don't qualify for a transplant (Sci. Transl. Med. 9 eaah5505).

The new approach builds on previous work in which the team created an engineered tissue scaffold for implantation into the abdomen of a mouse. However, those implants contained fewer than 1 million hepatocytes, while a healthy human liver has about 100  billion. To boost the hepatocyte population, the researchers exploited a key trait of liver cells: they can multiply to generate new liver tissue. They designed microfabricated structures containing spherical organoids of hepatocytes and fibroblasts, as well as cords of endothelial cells, and embedded these structures into fibrin. Once implanted into a mouse, regenerative signals from the surrounding environment stimulated the endothelial cells to form blood vessels and release factors that stimulate hepatocyte proliferation, resulting in 50-fold expansion of the original tissue. "The idea is that it's the seed of an organ, and you organize it in a way that it can be responsive to these regenerative signals," said Bhatia. "What's really exciting is that the architecture of the tissue that emerges looks a lot like the liver architecture in the body."

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