Transitional cell states at the crossroads of development, disease, and repair-regeneration

Cells undergoing transitional states have been broadly referred to as plastic intermediates emerging between stable identities in multiple biological contexts. Once regarded as indistinct midpoints on lineage trajectories, these states are now recognized as discrete, biologically meaningful epigenetically permissive states, exquisitely responsive to environmental and stress signals at critical junctures of biological events that confer competence to proceed along their trajectories. These high-plasticity nodes have emerged as central regulators of developmental progression and determinants of disease outcomes, serving as functional bottlenecks in which resolution or persistence dictates normal or maladaptive pathological responses. Recent single-cell and multiomics technologies enabled their detection with unprecedented resolution, revealing conserved regulatory themes, including stress-response activation and striking context dependence shaped by niche cues and tissue architecture. Yet challenges remain in capturing their rapid heterogeneous dynamic in the multiple contexts, and defining their function, in vivo. Here we summarize current concepts on the identification, diversity, role, and regulation of these cell states in events from early development to adult homeostasis, repair, and disease. The increasing recognition that transitional states can be productive conduits or pathological traps underscores their relevance in these processes and potential for the identification of therapeutic targets for intervention in disease, cancer, and regenerative medicine.