REGENECREST · Enhancing endogenous regenerative response in mammals by redeploying Cranial Neural Crest Cells pluripotency developmental programs and positional identity remodeling

Cell differentiation progresses via a continuous lineage restriction process where cell potential is reduced as the embryo develops. Pluripotent embryonic cells can beget all somatic cell types, but this capacity is rapidly restricted during the formation of the three germ layers, each giving rise to distinct cell types. Uniquely among vertebrates, a stem cell-like population arising in the embryo rostral part ? called cranial neural crest cells (CNCC) ? challenges this paradigm. CNCC not only give rise to ectoderm derivatives, such as neurons and glia, but also to cell types canonically associated with the mesoderm such as bone and cartilage of the face. During my postdoctoral training I demonstrated that murine CNCC naturally reverse cell differentiation to return into a pluripotent state during development. In addition, I showed pre-migratory CNCC carry positional information reflective of their spatial origin in the neuroepithelium. However, this identity is subsequently erased with migratory CNCC forming a transcriptionally homogenous population, which later re-diversifies as CNCC undergo commitment events. In my research proposal, using single-cell transcriptomics and genomics assays I seek to uncover and characterize gene regulatory networks and chromatin rearrangements regulating the reemergence of pluripotency programs within CNCC and the underlying reprograming of cellular identity. CNCC represent a unique model to study the molecular mechanisms governing cell-intrinsic behavior but also the role of the niche, which may influence the sequence of events by cell-cell interactions during craniofacial ontogeny. The interdisciplinary scope of experimental strategies included in this proposal will help understand how these fundamental processes are regulated and might result in novel strategies to stimulate craniofacial tissue repair, as cell dedifferentiation and reconfiguration of positional identity are two essential milestones for endogenous regeneration.