Comprehensive atlas of endothelial cells advances diabetes research

Comprehensive atlas of endothelial cells advances diabetes research

The diverse populations of endothelial cells that line blood vessels in the insulin-producing "islands" of the human pancreas have been notoriously difficult to study, but researchers at Weill Cornell Medicine have now managed to comprehensively detail the unique properties of these cells. The resulting atlas advances basic research into pancreatic biology and could lead to new treatment strategies for diabetes and other pancreatic diseases.

In the study, published Feb. 6 in Nature Communications, researchers developed a series of methods for rapidly isolating and profiling endothelial cells called ISECS (islet-specific endothelial cells) from donor pancreas. ISECs provide critical support for islet functions but die very quickly when separated from the pancreas using standard cell isolation techniques. With their highly optimized approach, the researchers were able to analyze large numbers of ISCs for the first time, mapping their molecular signatures and interactions with other pancreatic cell types.

The dataset generated in this study is the first to capture the full diversity of endothelial cells in the pancreas and we expect it to be an important resource for our and many other research groups. “

Dr. David Redmond, senior author, assistant professor of computational biology at the Hartman Institute for Therapeutic Organ Regeneration, Weill Cornell Medicine

Although the precise molecular signatures of ISECS were unknown, scientists had evidence that these cells support islet cell maturation, insulin secretion activities, and survival. They are also important for the long-term survival of islet transplants, which are rarely used to treat type 1 diabetes due to immune complications but could potentially be a cure if current obstacles are overcome.

For the study, the first author Dr. Rebecca Craig-Schapiro, an assistant professor of surgery at Weill Cornell Medicine and a transplant surgeon at NewYork-Presbyterian/Weill Cornell Medical Center who works closely with Hartman Institute members on deceased organ donors.

“Using our novel approach and using what is already known about ISECs, we were able to isolate and process these cells in very large numbers – more than 30,000 – as well as about 75,000 other pancreatic cells, allowing them all to be kept viable long enough to perform single-cell RNA sequencing,” said Dr. Craig-Schapiro.

The RNA sequencing data, which provides snapshots of gene activity in each cell, allowed the researchers to determine the characteristic gene activity signatures of ISECs as well as other pancreatic cells, including endothelial cells from the non-islet part of the pancreas.

“Using our RNA sequencing data, we were also able to identify support cells that communicate with ISECs and other endothelial cells in their respective pancreatic compartments,” said co-author Kevin Chen, a research technician in the Rafii lab.

Although previous studies of pancreatic cells, particularly for ISECs, were incomplete, the researchers noted that previous data largely matched their results wherever they overlapped.

“We were able to integrate our data with three other published datasets to provide detailed confirmation of our results and result in a much more complete cell atlas,” said co-author Dr. Ge Li, research associate in the Rafii laboratory.

Because insulin is produced in pancreatic islets, they are also a major focus for diabetes research. Using the new data along with existing data sets of gene activity in diabetic pancreatic tissue, the researchers cataloged endothelial genes and signaling pathways that appear to be disrupted in diabetes - and may be targets for future therapies.

“This comprehensive atlas provides us with a strong foundation for developing strategies to restore the function of ISECs and other cells in diabetes and other pancreatic diseases” Hartman Institute and the Ansary Stem Cell Institute and the Arthur B. Belfer Professor of Genetic Medicine at Weill Cornell Medicine.

Currently, the researchers are using their new atlas for several follow-on efforts, including developing techniques to produce ISECs from other cells, said Dr. Rafii, who is also a member of the Englander Institute for Precision Medicine, Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

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