This study investigates the dynamic regulation of tissue fluidity during skin repair following wound healing. The authors developed a mouse model that allows lineage tracing and basal cell lineage ablation, enabling them to monitor stem cell fate and tissue dynamics using confocal and intravital imaging. Key findings include: 1. **Dynamic Transitions in Tissue Fluidity**: The basal cell layer transitions from a solid-like homeostatic state to a fluid-like state during tissue remodeling, allowing for rapid repair. This transition is supported by mathematical modeling, which predicts density-dependent promotion of symmetric stem cell division. 2. **EGFR/AP1 Axis Regulation**: The EGFR/AP1 axis controls a regenerative state that regulates tissue fluidity and repair. Pharmacological inhibition of this axis impairs stem cell activation, clonal expansion, and tissue repair, suggesting its critical role in these processes. 3. **Transcriptional and Epigenetic Profiling**: Bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) reveal a common regenerative state in different epidermal stem cells (SCs) characterized by upregulation of genes involved in cell cycle, mitosis, and wound healing. This state is associated with increased chromatin accessibility and activation of AP1 transcription factors. 4. **Cellular Dynamics and Tissue Fluidization**: Intravital imaging shows that tissue fluidization, characterized by increased cellular rearrangements (T1 transitions), occurs during wound healing and basal cell lineage ablation. This fluidization facilitates rapid tissue repair by promoting clone fragmentation and basal cell dispersion. 5. **Mechanical and Biochemical Cues**: The study suggests that tissue fluidity activates signaling cascades through mechanical and biochemical cues, promoting the activation of a regenerative state. Inhibition of actomyosin contractility reduces T1 events and Jun/Fos expression, indicating that tissue fluidity initially promotes the activation of a regenerative state. Overall, the study provides insights into the complex interplay between cellular and molecular mechanisms, mechanical changes, and tissue fluidization during skin repair, highlighting the importance of the EGFR/AP1 axis in regulating these processes.This study investigates the dynamic regulation of tissue fluidity during skin repair following wound healing. The authors developed a mouse model that allows lineage tracing and basal cell lineage ablation, enabling them to monitor stem cell fate and tissue dynamics using confocal and intravital imaging. Key findings include: 1. **Dynamic Transitions in Tissue Fluidity**: The basal cell layer transitions from a solid-like homeostatic state to a fluid-like state during tissue remodeling, allowing for rapid repair. This transition is supported by mathematical modeling, which predicts density-dependent promotion of symmetric stem cell division. 2. **EGFR/AP1 Axis Regulation**: The EGFR/AP1 axis controls a regenerative state that regulates tissue fluidity and repair. Pharmacological inhibition of this axis impairs stem cell activation, clonal expansion, and tissue repair, suggesting its critical role in these processes. 3. **Transcriptional and Epigenetic Profiling**: Bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) reveal a common regenerative state in different epidermal stem cells (SCs) characterized by upregulation of genes involved in cell cycle, mitosis, and wound healing. This state is associated with increased chromatin accessibility and activation of AP1 transcription factors. 4. **Cellular Dynamics and Tissue Fluidization**: Intravital imaging shows that tissue fluidization, characterized by increased cellular rearrangements (T1 transitions), occurs during wound healing and basal cell lineage ablation. This fluidization facilitates rapid tissue repair by promoting clone fragmentation and basal cell dispersion. 5. **Mechanical and Biochemical Cues**: The study suggests that tissue fluidity activates signaling cascades through mechanical and biochemical cues, promoting the activation of a regenerative state. Inhibition of actomyosin contractility reduces T1 events and Jun/Fos expression, indicating that tissue fluidity initially promotes the activation of a regenerative state. Overall, the study provides insights into the complex interplay between cellular and molecular mechanisms, mechanical changes, and tissue fluidization during skin repair, highlighting the importance of the EGFR/AP1 axis in regulating these processes.