Lack of specificity of progenitor responses to injury in regeneration

Regeneration is the process by which organisms replace body parts lost to injury. How cell-type production after injury is tailored to match the identity of missing tissues is a central problem of regeneration. Here, we investigated the specificity of stem cell responses to the identity of missing tissues following injury in planarians. We find that proximal injury that does not affect the mature tissue nonetheless drives increased progenitor incorporation into spatially restricted neurons within the brain, the ventral nerve cords, as well as muscle and neurons within the pharynx. In response to direct injury, broadly distributed peripheral neurons show a generic amplification of incorporation within and outside of the injury. Body-wall muscle production was amplified with siphoning of muscle progenitor allocation from distal sites to the wound and proximal to the wound. By contrast, essentially no stem cell division contributes to the newly formed epidermis during initial regeneration, with the epidermis instead being derived from pre-existing post-mitotic progenitors. Large injury still amplifies epidermal progenitor production, which arrive at the epidermis weeks after injury, including to uninjured regions. These results indicate that the identity of the missing mature tissue has little impact on determining the specificity of the stem cell response to injury. We suggest that planarian regeneration involves a combination of ongoing cell turnover, wound-associated amplification of stem cells, and spatially broad neoblast specification zones. This yields a simple mechanism for regeneration specificity that returns missing cell types, but with imprecision, resulting in amplification of uninjured wound-proximal cell type production.