Partial reprogramming reveals lineage-specific uncoupling of rejuvenation, function, and recoverability in human cells

Partial reprogramming is therapeutically useful only if cells keep its benefits while recovering their lineage identity and function after the reprogramming factors are withdrawn. Whether the relationship between reprogramming depth and recovery differs between lineages is unknown. Using reversible, traceable Sendai-OSKM, we prospectively isolated intermediate reprogramming states from primary human fibroblasts, cytotoxic T cells, and aortic endothelial cells and followed their recovery. Outcomes diverged: fibroblasts kept a reduced DNA methylation age but retained stromal remodeling and incomplete proliferative recovery; T cells recovered only from shallow reprogramming, with enhanced effector function; endothelial cells rapidly recovered identity, kept a reduced methylation age, and markedly improved vascular function. None of this tracked iPSC derivation efficiency. Multiome and knockdown analyses identified TOX as a shared progression dependency, whereas its candidate downstream programs were predominantly lineage-specific. Partial reprogramming involves a lineage-specific tradeoff between rejuvenation and recovery that must be optimized one lineage at a time.