American scientists were able to restore glucose metabolism in diabetic mice using encapsulated beta cells grown from human stem cells (hSCs). The addition of CXCL12, an immune-cell-repelling protein, to microcapsules protected transplants from immune attack, preventing the accumulation of fibrous tissue.
“When islets are encapsulated in standard gel capsules, the inflammatory foreign body response causes a cellular overgrowth that ‘suffocates’ the encapsulated cells, leading to their failure”, – says lead author David Alagpulinsa, PhD, of the MGH Vaccine and Immunotherapy Center. “We found that mixing the immune-repellent protein CXCL12 into the capsule gel prevents this overgrowth from happening, prolonging the survival and function of the cells.”
The 2015 study, led by the director of the Vaccine and Immunotherapy Center Mark Poznansky, MD, PhD, described how capsules containing CXCL12 protein protected islet beta cells obtained from nondiabetic mice or pigs from immune rejection after transplantation into diabetic mice.
The encapsulated islets restored long-term blood sugar control in animals. It was also shown that the presence of CXCL12 repels T-cells associated with the rejection process, attracting regulatory T-cells that can suppress the immune response at the transplantation site.
The new study, published in American Journal of Transplantation, used insulin-producing beta cells derived from human pluripotent stem cells using a protocol developed by researchers at the Harvard Stem Cell Institute investigators led by Douglas Melton, PhD, co-author of current work.
These human beta cells were encapsulated with either low or high levels of CXCL12 prior to being transplanted into diabetic mice. During the entire study period, animals did not receive immunosuppressive drugs.
In mice that received cells in low-dose CXCL12 microcapsules, the blood sugar level returned to normal after two days, while in animals that had cells transplanted into microcapsules with high CXCL12 levels did not reach normal glucose levels for an average of seven days.
However, low-dose microcapsules with CXCL12 either failed or were rejected on the 100th day after transplantation. At the same time, beta cells grown from hSCs in high-dose CXCL12 microcapsules survived and continued fully functioning up to 154th day after transplantation, when the experiment was completed.
Next, scientists have learned and studied the microcapsules. Beta cells in capsules with a high level of CXCL12 demonstrated complete functionality and the virtual absence of cellular overgrowth. The low level of CXCL12 led to the proliferation of transplanted cells, which also lost their original characteristics of beta cells. The highest rate of overgrowth was observed in capsules not containing CXCL12.
“High levels of CXCL12 supported beta cell function and protected against both the immune response and the foreign body response significantly longer than did the lower CXCL12 concentration”, – says Poznansky, an associate professor of Medicine at Harvard Medical School.
“We previously explored the concentration dependence of this effect and showed how it can be related, in part, to differential activation of specific signaling pathways in immune and inflammatory cells by different levels of CXCL12 or similar proteins. Through the consistent support of the Juvenile Diabetes Research Foundation, we are currently exploring this mechanism and novel therapeutic approach in large animal models of type 1 diabetes.”
Alagpulinsa adds, “Unlike the previous study, this study uses human beta cells, and all the elements are biocompatible, which should facilitate the development of a clinical version of this product. The stem-cell-derived beta cells can be generated in unlimited quantities from both individuals with and without type 1 diabetes, and CXCL12 is a protein that is normally produced in pancreatic islets in the body.”