The known, unknown, and unknown unknowns of cell-cell communication in planarian regeneration

Planarians are the most primitive bilateral triploblastic organisms. Most planarian species retain the mechanisms for whole-body regeneration; for example, they can regenerate their cephalic ganglion after complete excision. This powerful whole-body regeneration capacity has made planarians model organisms in regenerative research for more than 240 years. The mysteries of planarian regeneration have been gradually uncovered while newly developed tools and techniques were applied. Exact cell-cell communication has long been understood to be a prerequisite for regeneration. In recent decades, the associated mechanisms have been uncovered at the cellular level. During planarian homeostasis and regeneration, stem cells (neoblasts) are the source of all new cells. The interplay between neoblasts and somatic cells affects the identities and proportions of various tissues during homeostasis and regeneration. Here, we review discoveries that scientists have sought to understand communications between stem cell compartments and other cell types in planarians, and the impact of communications on planarian regeneration. We also highlight challenges and future directions in planarian research, a field that has consistently contributed valuable knowledge of animal regeneration.