Identification of TOR-responsive slow-cycling neoblasts in planarians

Epimorphic regeneration commonly relies on the activation of reserved stem cells to drive new cell production. The planarian Schmidtea mediterranea is among the best regenerators in nature, thanks to its large population of adult stem cells, called neoblasts. While neoblasts have long been known to drive regeneration, whether a subset of neoblasts is reserved for this purpose is unknown. Here, we revisit the idea of reserved neoblasts by approaching neoblast heterogeneity from a regulatory perspective. By implementing a new fluorescence-activated cell sorting strategy in planarians, we identify a population of neoblasts defined by low transcriptional activity. These RNA^low neoblasts are relatively slow-cycling at homeostasis and undergo a morphological regeneration response characterized by cell growth at 48 h post-amputation. At this time, RNA^low neoblasts proliferate in a TOR-dependent manner. Additionally, knockdown of the tumour suppressor Lrig-1, which is enriched in RNA^low neoblasts, results in RNA^low neoblast growth and hyperproliferation at homeostasis, and ultimately delays regeneration. We propose that slow-cycling RNA^low neoblasts represent a regeneration-reserved neoblast population.