Loss of tissue-state plasticity: a conceptual framework for age-associated regenerative failure

Tissue regeneration depends on the activation of resident stem and progenitor cells, dynamic interactions with the extracellular matrix (ECM), and tightly regulated growth factor signaling, including fibroblast growth factors (FGFs) and transforming growth factor-β (TGF-β). Numerous therapeutic strategies have aimed to enhance repair through exogenous growth factor delivery or stem cell transplantation. However, despite the presence of abundant regenerative signals, including those derived from the senescence-associated secretory phenotype (SASP), regenerative capacity declines with age across multiple organs. This discrepancy suggests that age-related regenerative decline reflects not a reduction in signal availability, but a profound alteration in how tissues interpret and respond to those signals. Here, we propose a conceptual framework centered on the concept of "tissue state"-a metastable, tissue-wide organizational mode that determines how incoming signals are interpreted and executed. Tissue state is shaped by the integration of cellular composition, ECM properties, inflammatory context, and intracellular stress responses. Within this framework, exogenous signals are interpreted as context-dependent inputs, and their biological outcomes are determined by the pre-existing tissue state. We further discuss how this perspective reshapes our understanding of regenerative medicine, suggesting that restoring tissue-state flexibility may be a more effective therapeutic goal than simply augmenting signal availability.