The Woodruff School

SUMMARY

A functional cure for type 1 diabetes (T1D) could be stem-cell derived beta 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.

SUBJECT:	Ph.D. Proposal Presentation

BY:	Michael Hunckler

TIME:	Tuesday, January 12, 2021, 12:00 p.m.

PLACE:	https://bluejeans.com/135921159, 0

TITLE:	Synthetic Hydrogel-mediated Maturation and Engraftment of Human Pluripotent Stem Cell-Derived β-cells

COMMITTEE:	Dr. Andrés García, Chair (ME) Dr. Edward Botchwey (BME) Dr. Krish Roy (BME) Dr. Ankur Singh (ME) Dr. M. Cristina Nostro (Toronto)

SUMMARY A functional cure for type 1 diabetes (T1D) could be stem-cell derived beta 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.