A parenchymal niche regulates pluripotent stem cell function in planarians

Harnessing the extraordinary potential of stem cells requires exquisite control in vitro, in vivo, and in the context of potential therapies. Adult stem cells are commonly housed within a microenvironment, or "niche," that supplies signals to regulate stem cell function. It has been difficult to determine whether pluripotent stem cells have a similar endogenous niche due to the transient nature of the cell type in most animal species. We sought to establish the nature of a pluripotent stem cell niche using planarian flatworms, animals that maintain pluripotent stem cells throughout adulthood and use them for whole-body regeneration. We characterized the cellular microenvironment of planarian stem cells in detail, finding that each stem cell is surrounded by a diverse mixture of other stem cells and differentiated cells. We identified phagocytic cells marked by CTSL2 as the differentiated cell type most frequently found next to stem cells, in both homeostasis and regeneration. CTSL2 ⁺ cells, which we named abraçada cells, wrap around stem cells, and then neighbor progenitors less often coincident with their specialization. We then tested whether abraçada cells constitute a functional niche that regulates stem cells. We identified two innexin-encoding genes expressed in abraçada cells that are critical for pluripotent stem cell function and planarian regeneration. Together, our results reveal for the first time a local, endogenous niche that actively regulates adult pluripotent stem cells.