Improving Islet Transplantation to Treat Type 1 Diabetes

NIH Grant Funds Collaborative Effort to Engineer More Effective Cell Transplantation Approaches

To advance the field of cell transplantation, ISCRM investigators are testing a novel method of keeping harmful immune cells at bay while allowing the good immune cells to heal the injury

Degenerative diseases come in many forms. When they strike, the root cause is essentially the same: unchecked cell depletion that impairs the functioning of tissues and organs. In type 1 diabetes, for example, the body’s immune system attacks beta cells, a special type of cell in the pancreas that produces insulin, the hormone we rely on to regulate blood-sugar levels.

Today, 1.25 million adults and children with type 1 diabetes rely on insulin for day-to-day survival. For years, researchers have experimented with more permanent fixes, including transplanting pancreatic islets, which contain insulin-producing cells, into patients.

Widespread use of this cell replacement therapy for type 1 diabetes and other degenerative diseases faces multiple obstacles. First, there is a shortage of biological material. There simply aren’t enough viable cells from organ donors to meet the demand. Second, transplanted tissue has to take root in order to survive. That requires rapid revascularization. Third, the foreign tissue must be protected from the immune system that turned against the pancreas in the first place.

Overcoming those obstacles requires creative collaboration, major funding, and an ambitious idea backed by preliminary data. Now, thanks to an R01 grant from the NIH, a research team from UW Institute for Stem Cell and Regenerative Medicine (ISCRM) has all three tools to take on these long-standing challenges in transplantation.

Laura Crisa MD, PhD, Associate Professor of Medicine/Pharmacology, Metabolism, Endocrinology & Nutrition, is the lead investigator on the project, which is now sustained by a 4-year, $2 million grant from the National Institute of General Medical Sciences (NIGMS). Crisa emphasizes that the real work began several years ago when she and her ISCRM colleague Cole DeForest PhD, Assistant Professor of Chemical Engineering and Bioengineering, received a pilot grant from ITHS (Institute of Translational Health Science) and an Innovation Pilot Award from ISCRM to gather the data they would need to apply for federal funding.

Laura Crisa MD, PhD, Associate Professor of Medicine/Pharmacology, Metabolism, Endocrinology & Nutrition

These early awards allowed Crisa and DeForest to work through multiple rounds of trial-and-error experiments before arriving at the proof-of-concept stage – a critical threshold for scientific research. It is just one example of a resounding return-on-investment that began three years ago. Since the IPA program was made possible by the State of Washington in 2017, award recipients have drawn millions of dollars in federal research grants to the University of Washington.

Today, the partnership is a triumvirate. Joining Crisa and DeForest in the pursuit for a more perfect (transplanted) pancreas is Vincenzo Cirulli, MD, PhD, Associate Professor of Medicine/Pharmacology, Metabolism, Endocrinology & Nutrition. Together, the three investigators are eager to use their combined expertise in islet and stem cell biology, vascular biology and cellular immunology, and biomaterials to significantly improve the wellbeing of people with type 1 diabetes.

Using Biomaterials to Improve Vascuarization and Prevent Inflammation

Crisa describes the hurdles. “Number one, we have to accelerate vascularization after transplantation. More than 30% of grafts die within 48 hours due to lack of blood supply. Number two, we have to keep harmful immune cells at bay while allowing the good immune cells to heal the injury. To do that, we need a material that allows us to “control” the engraftment process.” In other words, says Crisa, a tool that drives new vessels toward the islet transplant and repels well-intended, but harmful inflammatory cells.

Vincenzo Cirulli, MD, PhD, Associate Professor of Medicine/Pharmacology, Metabolism, Endocrinology & Nutrition

One key sticking point is that blood vessels, essential for life, are also channels for the immune system. That presents an inherent challenge: how to deliver vital nutrients that enable the healthy cells to become the productive insulin factories the researchers want while preventing unwanted inflammation and, ultimately, rejection of the new tissue.

Cirulli explains another unique challenge. “Normally, in the human pancreas, islets develop over 39 weeks. With stem cells, we are trying to compress nine months into three or four weeks in a dish. Stem cells need the proper cues to quickly mature into the right type of cells. And for stem cell-derived islet tissue it is important that the cells continue to receive the right signals at transplantation site so that the tissue functions properly – that it  senses glucose and secretes insulin. The special scaffolds we are going to test will allow us to precisely deliver these critical cues to the transplant site.”

According to DeForest, the ISCRM team is trying a new twist on an old technique. “Other research efforts have tried to insulate healthy cells from aggressive immune cells by encasing them  in synthetic materials. Our scaffolding technology enables us to customize the biomaterials with  biochemical and physical cues that attract blood vessels while discouraging attacks from immune cells.”

Improving Islet Transplantation in the Clinic

Faculty headshot of Cole DeForest, PhD
ISCRM faculty member Cole DeForest PhD is applying his expertise in biomaterials to helping people with type 1 diabetes and other diseases of cell depletion.

The true novelty is in the details. Advances in the fields of tissue engineering and biomaterials make it possible to both create and regulate nurturing environments for cells. The x-factor for Crisa, DeForest, and Cirulli are special proteins that they have identified in the developing pancreas.

These proteins promote vascularization, help progenitors of pancreatic beta-cells mature, and mitigate immune response by controlling both the thickness of the scaffold and special proteins that repel immune cells. “There is data that shows whether a tissue is stiff or soft affects vascularization, growth, maturation, and differentiation,” says Cirulli. “We believe that adding these special regulator proteins will help us do this, like a drug.”

The researchers also point to the role ISCRM has played. In addition to the early funding from the Innovation Pilot Award, simply being a part of a collaborative research community was important, says DeForest. “This grant brings together a unique combination of skill areas, and I think it’s safe to say that ISCRM helped make that happen. It shows that intentionally bringing together labs from different areas of medicine and engineering works.”

Success could lead to exciting progress, says Cirulli. “If this works, it can be immediately translated to the clinical setting to improve human islet transplantation that is already happening. Learning how to grow islets from stem cells would also provide a replenishable source of tissue to transplant into patients waiting for treatment and have applications for a wide range of medical conditions requiring cell replacement therapies.”