Engineered blood vessel cells boost islet transplant success in diabetes treatment

Adding engineered human blood vessel-forming cells to islet transplants boosted the survival of the insulin-producing cells and reversed diabetes in a preclinical study led by Weill Cornell Medicine investigators. The new approach, which requires further development and testing, could someday enable the much wider use of islet transplants to cure diabetes.

Islets, found in the pancreas, are clusters of insulin-secreting and other cells enmeshed in tiny, specialized blood vessels. The insulin cells are killed by an autoimmune process in type 1 diabetes, which affects roughly nine million people worldwide. Although islet transplantation is a promising approach for treating such cases, the only FDA-approved method to date has significant limitations.

In a study published Jan. 29 in Science Advances, the researchers showed that special blood vessel-forming cells they developed, called "reprogrammed vascular endothelial cells" (R-VECs), can overcome some of these limitations by providing strong support for islets, allowing them to survive and reverse diabetes long-term when transplanted under the skin of mice.

"This work lays the foundation for subcutaneous islet transplants as a relatively safe and durable treatment option for type 1 diabetes," said first author Dr. Ge Li, a postdoctoral research associate in the laboratory of senior author Dr. Shahin Rafii, director of the Hartman Institute for Therapeutic Organ Regeneration and the Ansary Stem Cell Institute, chief of the division of regenerative medicine and the Arthur B. Belfer Professor in Genetic Medicine at Weill Cornell Medicine. Dr. Rafii is also a member of the Englander Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

The currently approved islet-transplant method infuses islets into a vein in the liver. This invasive procedure requires the long-term use of immune-suppressing drugs to prevent islet rejection, involves the relatively uncontrolled dispersal of islets, and usually becomes ineffective within a few years, likely in part to the lack of proper support cells. Ideally, researchers want a method that implants islets in a more controlled and accessible site, such as under the skin, and allows the transplanted tissue to survive indefinitely. Researchers also hope eventually to sidestep the immune rejection problem by using islets and endothelial cells that are derived from patients' own cells or are engineered to be invisible to the immune system.

In the new study, Drs. Li and Rafii and their colleagues demonstrated the feasibility of long-term subcutaneous islet transplants using R-VECs as critical support cells. "We showed that vascularized human islets implanted into the subcutaneous tissue of mice that were immune-deficient promptly connected to the host circulation, providing immediate nutrition and oxygen, thereby enhancing the survival and function of the vulnerable islets," said Dr. Rafii. Indeed, derived from human umbilical vein cells, R-VECs are relatively durable in transplant conditions—unlike the fragile endothelial cells found in islets—and are engineered to be highly adaptable, supporting whatever specific tissue type surrounds them.

Remarkably, we found that R-VECs did adapt when co-transplanted with islets, supporting the islets with a rich mesh of new vessels and even taking on the gene activity "signature" of natural islet endothelial cells."

Dr. David Redmond, assistant professor of computational biology research in medicine, Hartman Institute for Therapeutic Organ Regeneration

A substantial majority of diabetic mice transplanted with islets-plus-R-VECs regained normal body weight and showed normal blood glucose control even after 20 weeks—a period that for this mouse model of diabetes suggests an effectively permanent islet engraftment. Mice that received islets but no R-VECs fared much less well.

The team showed in the study that the islet cell and R-VEC combinations also can grow successfully in small "microfluidic" devices—which can be used for the rapid testing of potential diabetes drugs.

"Ultimately, the potential of surgical implantation of these vascularized islets needs to be examined for their safety and efficiency in additional preclinical models," said co-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. Dr. Craig-Schapiro is also associated with the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine.

"Nonetheless, translation of this technology to treat patients with type 1 diabetes will require circumventing numerous hurdles, including scaling up sufficient numbers of vascularized islets, and devising approaches to avoid immunosuppression," said Dr. Li.  This study is the first step to achieve these goals, which could be within reach in the next several years.