A major aim of this grant is to investigate the developmental origin of the skeleton-forming cells in the head, as well as their ability to regenerate craniofacial skeleton in adults after injury. The head skeleton derives from a special population of cells, the neural crest, which has the remarkable ability to form not only neurons but also skeletal tissues. We had previously identified a unique role of histone replacement within the neural plate precursor cells that allows neural crest to make skeletal derivatives. In the current grant cycle, we now find that misexpression of groups of neural plate transcription factors is able to convert cells to a neural crest fate, and we are currently exploring whether this occurs by stimulating the histone replacement program we found to be so important for neural crest development. We are also testing whether similar neural plate transcription factors can convert mammalian cells to a neural crest fate, with the eventual goal to use this technique to generate an unlimited supply of patient-specific bone and cartilage replacement cells for skeletal repair.
A parallel strategy that we are taking towards regenerative strategies for facial skeleton is to stimulate endogenous neural crest cells to make replacement skeleton. While we have a limited ability to repair defects in our skeleton, for example after bone fracture, we have found that adult zebrafish have the remarkable ability to regenerate nearly their entire lower jawbone following amputation. By studying why zebrafish regenerate facial skeleton to a much greater extent than humans, we hope to devise molecular strategies to augment skeletal repair/regeneration in patients. In particular, we have found that during zebrafish lower jawbone regeneration, cartilage cells are able to change their fate to directly make replacement bone, which is in marked contrast to the way bone is made during development. We have also identified a critical role of the Ihh signaling pathway in bone regeneration and in particular the generation of the critical cartilage intermediate. In adults lacking the Ihha protein, no cartilage forms after jawbone amputation and the jawbone fails to heal properly. Moreover, in collaborative work we find that such bone-producing cartilage cells may also be present in a mammalian model of bone healing. We are therefore excited by the prospects of using similar bone-producing cartilage cells to repair large skeletal wounds in patients.