A Team Science Approach to the Co Development of Oral Mucosa for Therapeutic Purposes

The oral cavity soft tissues protect against pathogens, toxins, and trauma. Over 100,000 soft tissue grafts are performed annually in the U.S. after trauma or biopsy. Current approaches, including autologous grafts, allografts, and xenografts, have significant limitations. Autologous mucosal equivalents derived from induced pluripotent stem cells (iPSCs) could overcome these obstacles. In this application, we propose to bioengineer vascularized, functional grafts that can be tailored to diverse clinical needs. We have assembled a team whose members have defined the fundamental principles of renewal in the oral mucosa, identified key progenitor populations in both mouse and human, and established pioneering advances in bioengineering to enable translation to patients. We propose a guided approach that integrates single cell/spatial multiomics, developmental biology, stem cell biology, and bioengineering to address three specific aims. First, we will build on our molecular atlas of oral tissues to identify additional pathways that regulate oral epithelial lineage decisions through interaction with peri-epithelial fibroblasts. Second, we will develop and optimize protocols to produce iPSC-derived oral epithelial and mesenchymal populations for tissue engineering. Third, we will engineer vascularized, autologous oral tissue rudiments ready for soft tissue grafting. At the end of the project, we will have generated scalable, vascularized, autologous grafts that mimic keratinized and non-keratinized mucosa that we expect to reduce rejection and improve outcomes, positioning us to move towards applications in the clinic. Project Number: 1RM1DE035338-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Ophir Klein (+2 co-PIs) | Institution: CEDARS-SINAI MEDICAL CENTER, LOS ANGELES, CA | Award Amount: $1,240,877 | Activity Code: RM1 | Study Section: Special Emphasis Panel[ZDE1 CC (10)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11235023