Modular regulation of the stem cell transcriptome defines self-renewal, differentiation, and dedifferentiation

Adult stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. Stem cells themselves are frequently replenished by dedifferentiation of partially differentiated progeny. It is a paradox how stem cells and progeny retain the same potential to be or become stem cells, while undergoing different trajectories of self-renewal, differentiation, and dedifferentiation. Here, we show that Drosophila male germline stem cells (GSCs) solve this paradox via two parallel mechanisms. First, differentiating progeny (spermatogonia) may maintain dedifferentiation-competence by inheriting the transcriptome from GSCs in the form of perdurant mRNA, without actively transcribing these genes. Second, two niche signaling pathways (Bmp and Jak-Stat) activate overlapping but distinct subsets of transcriptional targets, and their combinatorial activity allows equally-potent cells to choose different trajectories. Together, this study reveals how a pool of dedifferentiation-competent progeny is maintained to regenerate stem cells as needed without resulting in tumorigenic stem cell overproduction.