Project Summary/Abstract Trauma- and cancer-induced tissue damage is common in the mandible. Critical failures associated with current grafting treatments, like osteonecrosis, occur due to poor local conditions and limited integration between the graft and the host tissue. Recent studies show that cartilage grafts produce well-vascularized and integrated bone regeneration similar to an isograft, indicating that chondrocytes can form bones. As a mechanism, cell trans-differentiation from chondrocytes into bone cells has been demonstrated. Yet, membranous osteogenesis is currently considered the sole mechanism in the formation and repair of mandible body, despite two types of cartilage (Meckel’s cartilage, MC; and Rostral Process, RP) present during mandible growth. Similar to the mouse model, a RP-MC-like structure is identified in human fetuses and infants. To address whether endochondrogenesis contributes to the growth and repair of mandible body, a series of studies using complementary approaches has been performed. The key findings are: 1) the mandible body is composed of both membranous and endochondral bones; 2) hypertrophic chondrocytes in MC and RP directly trans- differentiate to bone cells instead of directly entering apoptosis; 3) RP-MC is one continuous cartilage; 4) a new Condensed Mesenchymal Progenitor (CMP) zone is identified, which provides new cell sources for RP and MC expansion; and 5) endochondrogenesis plays a key function in the mandible repair via a switch mechanism from the default program (membranous bone) to a trauma repair program (endochondral bone), where chondrogenesis (with limited requirement of angiogenesis) occurs first, followed by chondrocyte trans- differentiation into bone. Based on these findings, the central hypothesis is that the mandible body is composed of both endochondral and membranous bones, and that endochondrogenesis plays a key role in mandible repair. To test this central hypothesis, three highly related, yet independent Specific Aims are proposed: 1) To determine how MC and RP contribute to mandible formation via chondrocyte trans-differentiation; 2) To delineate the mechanism by which RP is derived from the CMP, and the CMP-RP, a growth-plate like structure, converges and elongates the two ends of MCs during mandible growth at cellular and molecular levels; 3) To determine how endochondrogenesis contributes to mandible repair via a switch mechanism from the default development program (membranous bone) to a trauma repair program (endochondral bone) through a change in the stem cell fate. Completion of this project will 1) demonstrate that the CMP-RP-MC complex contributes to mandible growth via the trans-differentiation of RP-MC chondrocytes into bone cells; and 2) identify some of key factors that are responsible for the switch from membranous osteogenesis to endochondrogenesis via a change of the stem cell fate in the repair process. These results will likely revise the current concept, provi...