Cellular plasticity and lineage in mammalian digit tip regeneration

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PROJECT SUMMARY Mice, monkeys, and humans can regenerate their digit tips following amputation. This innate form of composite tissue regeneration is a highly coordinated process involving multiple tissue types interacting to form a replacement digit tip with the proper composition and pattern. Defining what is unique to the digit tip in terms of molecular signals or cell types, and how it relates to regeneration, can inform broader regeneration efforts of non-regenerative tissues. One foothold into this process is the recent cellular characterization of the mouse digit tip blastema, the collection of progenitor cells that forms following amputation that is necessary to give rise to the regenerating tissue. Our single cell RNA sequencing-based analysis of the blastema identified 13 molecularly distinct fibroblast populations. With this, we now have specific cellular populations to individually assess for their function(s) in digit tip regeneration. We propose that the subpopulations of fibroblasts in the regenerating mouse digit tip encompass separable roles including progenitors, structural, and niche-factor- producing cells, of which a subset may promote composite tissue regeneration. In this proposal, we focus on digit tip fibroblast heterogeneity and aim to determine the origin, function, and regenerative potential of each of these populations. We will analyze the spatial organization of the fibroblast subpopulations in mouse and human digit tips and determine those comprised of progenitor cells. Using single cell RNA sequencing with lineage tracing, we will determine when the digit tip heterogeneity of the adult digit is established, and define the cellular plasticity and regenerative contribution of the fibroblast populations to the regenerated tissue. Finally, we will investigate how the digit tip fibroblast subpopulations relate in identity and function to fibroblasts from non-regenerative proximal amputations. Collectively, the data generated in this project will provide a comprehensive understanding of the heterogeneous population of digit tip fibroblasts in the context of regeneration, which will lay the foundation for composite tissue regeneration on a broader scale.