Post-transcriptional regulation of planarian stem cells drives whole-body regeneration

Planarians are freshwater flatworms that can regenerate any part of their body including an entire head. A single transplanted planarian pluripotent stem cell can rescue a lethally irradiated animal. Hence, the extreme plasticity of planarian stem cells is critical for regeneration. Despite intensive research, we still do not understand how cellular mechanisms that regulate planarian stem cell homeostasis are integrated to facilitate regeneration. We identified that the mRNA modification pathway N6-methylation of adenosine (m6A) is critical for normal planarian stem cell function, and that animals lacking an active m6A pathway fail to regenerate. Defects in stem cell function following inhibition of the mRNA modification pathway suggest that the highly conserved m6A pathway is an essential regulator of planarian stem cell plasticity. Moreover, it is required for the homeostasis of the entire stem cell population. Using functional studies of mRNA modification pathway genes, we identified the stem cell functions that are regulated by mRNA modifications and their roles in the generation of different cell lineages. Our findings reveal critical roles for mRNA modifications in the regulation of regeneration and tissue turnover, which underlie the amazing capacity of planarians to survive injuries.