Synthetic hydrogels recapitulate epithelial morphogenesis programs

Abstract

Understanding the contributions of the ECM biophysical and biochemical properties to epithelial cell responses has been a major goal for biomaterials scientists in order to engineer materials that can recapitulate ECM-mediated epithelial morphogenesis programs. Although 3D natural matrices have been found suitable for the study of many cellular processes, they are limited by lot-to-lot compositional and structural variability, inability to decouple mechanical and biochemical properties, and in some cases, their tumor-derived nature limits their clinical translational potential. Therefore, there is a significant need for a biomaterial matrix that can recapitulate epithelial morphogenetic programs while overcoming these limitations. This project aims to develop an engineered synthetic hydrogel matrix that presents independently-tunable basement membrane-like bioactivity and mechanical properties, and can support epithelial cell survival, proliferation, polarization, and assembly into 3D multicellular structures recapitulating different epithelial morphogenesis program. This synthetic material has the capacity to present adhesive peptides and protease-degradable crosslinks that support cell functions and promote cell engraftment in vivo. As part of this project, we have developed an engineered synthetic hydrogel platform that recapitulates the morphogenetic program of human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs), and has been established as a delivery vehicle for HIOs to mucosal intestinal wounds in mice. Furthermore, in order to prove the versatility of our hydrogel platform, we aim to engineer a synthetic hydrogel that recapitulates the mouse inner medullary collecting duct (IMCD) cell morphogenetic program. We hypothesize that these engineered hydrogels will be superior to naturally-derived materials by supporting these different epithelial morphogenetic programs while overcoming the imitations of natural and other synthetic materials. This synthetic hydrogel technology is significant as it allows the study of the independent contributions of ECM properties to different epithelial morphogenetic programs, and will form a basis for the adaptation to in vitro generation and in vivo delivery of human PSC-derived organoids for regenerative medicine.