Developmental plasticity of stem cells in teeth and taste bud renewal

Abstract

Science and medicine have progressed in unfathomable ways over the past century. Paradoxically, as our result of our advancements in medicine we live in a progressively aging society where the majority of people will have multiple morbidities associated with senescence. The World Health Organization estimates that nearly 100% of the population will suffer dental maladies, which left untreated compound with age. We hope to gain new biomedical insight applicable to the advancing field of dental regenerative therapeutics. This dissertation reveals new dental biology through studying the embryology, genetics and evolution of teeth across patterning, morphogenesis and regeneration. We exploit an innovative model, the Lake Malawi cichlid fishes, to study these processes in a natural system. Malawi cichlids have rapidly evolved diverse species-specific dentitions, ranging from hundreds to thousands of teeth that represent a rainbow of shapes and sizes, yet Malawi cichlid species has nearly identical genomes, offering us a powerful genetic system. Furthermore, unlike classic vertebrate models in embryology such as zebrafish, chicken or mice, cichlids have oral teeth and the ability to replace each tooth constantly throughout their lifetimes. In the first study, we break-down the process of whole de-novo tooth replacement in cichlids. We then explore the re-deployment of initiating gene pathways later in the morphogenesis of each replacement tooth (RT). In the second study we investigate the co-patterning of two placode derived oral organs, teeth and taste buds (TBs), and uncover new genes that may modulate their number and size. We subsequently discover a bipotency of progenitor tissue to form both organs and a later plasticity to trans-fate it through coordination of a Wnt-BMP- Hh genetic hierarchy. In the last study, we explore the stem cells that are responsible for the phenomenon of lifelong cichlid tooth replacement. We describe a common epithelium connected to TBs and rich in stem cells, with a newly discovered stem cell niche at the tip of the RT. We uncover the transcriptomes of both organs, and through differential gene expression informed manipulations, coerce dental cells to display TB characteristics. We hypothesize that TB stem cells may be used in dental therapeutics.