Nonlinear Dynamics of Collagen Turnover Reveal Distinct States of Fibrosis and Regeneration After Cardiac Injury

Replacement cardiac fibrosis is accompanied by extensive extracellular matrix remodeling, which can lead to either irreversible fibrosis or functional regeneration. Here, experimental measurements are integrated with nonlinear dynamic modeling to characterize how the temporal coupling between collagen synthesis and deposition contributes to divergent remodeling outcomes. Using an acute β-adrenergic receptor agonist-induced cardiac injury model in mice, we quantified temporal changes in the most abundant fibrillar collagens and the total deposited collagens during inflammatory, proliferative, and reparative phases. Complementarily, proteomic data from zebrafish ventricular amputation were used to map collagen turnover during regenerative healing. Ordinary differential equation-based models were developed to represent collagen mRNA synthesis, protein deposition, and their coupling across time to interpret fibrosis in mice. The model exhibited steep collagen accumulation followed by saturation, reflecting a stable fibrotic fixed point. In contrast, zebrafish exhibited early collagen degradation and subsequent restoration toward baseline levels, consistent with regenerative remodeling. Phase-space and stability analyses revealed distinct steady-state behaviour, where identical initial conditions diverged toward either a fibrosis-dominant or regeneration-dominant attractor state for two different systems, concurring with similar non-linearity observed in gold-standard ligation-mediated fibrosis and cryoinjury-mediated regenerative models. Coupled dynamics in mice further revealed nonlinear, history-dependent relationships between collagen synthesis and deposition. Together, these findings identify collagen turnover as a key driver of emergent tissue-level states, providing a unified quantitative framework that links cellular signaling to the macroscopic outcomes of cardiac repair.