PI: Dr. Laura Crisa
Location: Institute for Stem Cell & Regenerative Medicine
Modeling revascularization and leukocyte trafficking to immune privileged tissues by Slits signaling
One of the most significant challenges of cell replacement therapies for the treatment of Type 1 diabetes is the design of immunoregulatory strategies that promote the engraftment, survival and function of pancreatic islet cell transplants and overcome their immune rejection. Our laboratory has identified several extracellular cues that recapitulate an in vivo-like immune-privileged microenvironment and that promote cell transplant engraftment and function. Most recently, we discovered that neurotropic factors of the Slit family are expressed in the pancreatic islet niche and that their recognition by Robo receptors is involved in the regulation of endocrine cell identity, vascularization, and immune isolation from trafficking leucocytes.
Based on these data, and on the notion that Slits exhibit a repulsive function on leukocytes, we postulate that Slits expressed in pancreatic islets may a) recruit endothelial cells into developing islet cell clusters thereby regulating the formation of blood vessels within these endocrine organelles, and b) “segregate” pancreatic islets from circulating immune cells, thereby contributing to the establishment and maintenance of immune tolerance to these organelles.
To test this hypothesis, we will adopt an innovative approach developed by our collaborators at the Institute for Protein Design (University of Washington) to bioengineer synthetic protein sheets containing Slits’ binding domains that will be used both in ex vivo studies of islet cell maturation, and in experiments of transplantation designed to exploit the pro-angiogenic functions of Slits and their anti-leukocyte trafficking at sites of cell transplant engraftment. We anticipate that these studies may lead to the design of novel strategies for the bioengineering of tissue niches that will promote islet cell transplant engraftment and function, while evading immune recognition.