Dr. Andrés García (ME, Georgia Institute of Technology)
Dr. Edward Botchwey (BME, Georgia Institute of Technology)
Dr. Krish Roy (BME, Georgia Institute of Technology)
Dr. Ankur Singh (ME, Georgia Institute of Technology)
Dr. M. Cristina Nostro (University of Toronto)
Synthetic Hydrogel-mediated Maturation and Engraftment of Human Pluripotent Stem Cell-Derived β-cells
A functional cure for type 1 diabetes (T1D) could be stem-cell derived β-cell replacement to restore the insulin-producing β-cells that were destroyed by autoimmune system. Human pluripotent stem cells (hPSCs) can differentiate into insulin-producing monohormonal cells that phenotypically and functionally resemble immature β-cells. While promising, fully functional in vitro differentiation of these hPSCs into mature β-cells remains elusive. Current in vitro differentiation protocols of hPSCs cannot provide the precise microenvironmental cues necessary for complete maturation. Consequently, in vivo implantation is often used to direct end-stage maturation of stem cells, resulting in an uncontrolled environment to direct β-cell maturation. Furthermore, there are few suitable delivery vehicles for transplantation to clinically-translatable extrahepatic sites. These challenges highlight the need for strategies that enhance the in vitro maturation of the hPSC-derived β-cells and improve their engraftment and function in a clinically-translatable transplant site. The objective of this project is to engineer advanced synthetic hydrogels to direct in vitro maturation and function of hiPSC-derived β-cells and enhance engraftment and vascularization in an extrahepatic murine transplant site. This will be achieved through two specific aims: (1) human induced pluripotent stem cells (hiPSCs) will be encapsulated in engineered synthetic hydrogels that direct the in vitro differentiation to a mature β-cell stage. Encapsulated β-cells will be evaluated for their viability, function, and maturation. (2) Pancreatic progenitors and immature β-cells will be transplanted into the clinically-relevant, extrahepatic gonadal fat pad with synthetic vasculogenic hydrogels to promote β-cell engraftment, maturation, and function. This project will provide a significant foundation for translation of hiPSC-derived β-cells into more clinically-relevant sites and establish innovative materials that promote survival, engraftment, and function of hiPSC-derived β-cells.