Progenitor cell formation from connective tissue during Axolotl limb regeneration

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Adult salamanders display functional regeneration of organs such as the eye, lower jaw, limb and tail, while mammals have lost this capacity. Which extracellular and intracellular factors determine a non-regenerative versus regenerative response to injury? In non-regenerating organisms, the wound site is infiltrated by connective tissue fibroblasts that contract the wound together, but these cells form scar tissue rather than replacing lost tissue. In contrast, during limb regeneration the connective tissue produces multipotent progenitor cells that express developmental genes and regenerate patterned skeleton. This proposal addresses how injury causes the salamander limb connective tissue to produce a multipotent progenitor cell that expresses developmental genes. Using cell tracking we will determine if connective tissue fibroblasts and cartilage dedifferentiate to a progenitor cell state, or whether a resident stem cell is selectively amplified. We will then determine which extracellular signals promote the formation of the progenitor cells. Finally, we will determine the epigenetic changes that occur at the genomic loci of developmental genes in the regenerating connective tissue.