The transdifferentiation of cardiac fibroblasts into myofibroblasts after cardiac injury has traditionally been defined by a unidirectional continuum from quiescent fibroblasts, through activated fibroblasts, and finally to fibrotic-matrix producing myofibroblasts. However, recent lineage tracing and single cell RNA sequencing experiments have demonstrated that fibroblast transdifferentiation is much more complex. Growing evidence suggests that fibroblasts are more heterogenous than previously thought, and many new cell states have recently been identified. This review reexamines conventional fibroblast transdifferentiation paradigms with a dynamic state space lens, which could enable a more complex understanding of how fibroblast state dynamics alters fibrotic remodeling of the heart. This review will define cellular state space, how it relates to fibroblast state transitions, and how the canonical and non-canonical fibrotic signaling pathways modulate fibroblast cell state and cardiac fibrosis. Finally, this review explores the therapeutic potential of fibroblast state space modulation by p38 inhibition, yes-associated protein (YAP) inhibition, and fibroblast reprogramming.

心脏损伤后心脏成纤维细胞向肌成纤维细胞的转分化传统上定义为从静止成纤维细胞到活化成纤维细胞，最后到产生纤维化基质的肌成纤维细胞的单向连续体。然而，最近的谱系追踪和单细胞 RNA 测序实验表明，成纤维细胞转分化要复杂得多。越来越多的证据表明，成纤维细胞比以前认为的更异质，并且最近发现了许多新的细胞状态。这篇综述用动态空间透镜重新审视了传统的成纤维细胞转分化范式，这可以更复杂地理解成纤维细胞状态动力学如何改变心脏的纤维化重塑。这篇综述将定义细胞状态空间，它如何与成纤维细胞状态转换相关，以及经典和非经典纤维化信号通路如何调节成纤维细胞状态和心脏纤维化。最后，本综述探讨了通过 p38 抑制、yes 相关蛋白 (YAP) 抑制和成纤维细胞重编程来调节成纤维细胞状态空间的治疗潜力。