Abstract Body: Background: Fibroblasts regulate tissue remodeling following injury but are primarily viewed as drivers of fibrosis. Whether they adopt distinct functional states that differentially regulate inflammation, fibrosis, and repair across tissues remains unclear.

Hypothesis: Fibroblast plasticity generates functionally distinct states that coordinate host responses to tissue injury, infection, and repair.

Methods: Using complementary pulmonary and cardiac models, we combined transcriptional profiling, lineage tracing, and functional analyses. In the lung, fibroblast responses were examined following Aspergillus fumigatus challenge. In the heart, a reversible stress model was used with angiotensin II and phenylephrine infusion (2 weeks) followed by withdrawal. Fibroblast states were further interrogated using matrix stiffness–dependent reprogramming in vitro.

Results: In pulmonary injury, fibroblasts adopted an activated state associated with immunomodulatory and extracellular matrix–related gene programs. In the heart, transient stress induced fibrosis that resolved following withdrawal. Lineage tracing demonstrated that activated fibroblasts persisted during recovery and transitioned into a distinct non-fibrotic, reparative-like state rather than being eliminated. This population exhibited reduced expression of pro-fibrotic markers and enrichment of immune-modulatory pathways. Similar state transitions were observed in vitro in response to changes in matrix stiffness. These findings indicate that fibroblast states exist along a dynamic continuum spanning inflammatory, fibrotic, and reparative programs rather than fixed phenotypes.

Conclusions: Together, these findings support a unified framework in which fibroblast plasticity generates interconnected states that orchestrate tissue responses across organ systems. Defining these transitions provides a foundation for targeting fibroblast programs to modulate inflammation and fibrosis.