Topological laser delivery induces efficient regeneration via a transient cell network with super activation of hepatocyte growth factor

Summary: Abstract Body: Effective tissue regeneration relies on transient activation of cellular signaling networks post-injury. Here, we unveil that fractional CO2 laser treatment induces a quorum sensing-like regenerative response in mammalian skin, orchestrated by macrophage-fibroblast crosstalk. Using optimized laser parameters (3.6 mJ energy, 10% density), we observed synchronized hair regeneration across both ablated and non-ablated regions, triggered by surpassing a critical injury threshold. Transcriptomic analyses identified hepatocyte growth factor/scatter factor (HGF/SF) as a pivotal mediator. Post-laser injury, macrophages act as sensors, secreting HGF/SF to recruit additional macrophages into non-ablated regions and initiating crosstalk with fibroblasts. These interactions stimulate fibroblast to produce more HGF/SF, amplifying macrophage recruitment and further enhancing regenerative signaling (modulator, self-amplifying). Subcutaneous HGF/SF delivery activates telogen-anagen transition of HF stem cells and induce robust hair growth (actuator, when signals are over quorum sensing threshold). Inhibition of the c-Met receptor delayed hair growth. Clinical studies in patients with androgenic alopecia revealed increased hair density (from 90 hairs/cm2 to 135 hairs/cm2) following fractional CO2 laser treatment is accompanied by elevated HGF/SF expression from M2 macrophages and fibroblasts. These findings imply that HGF/SF work as a central coordinator, orchestrating macrophage-fibroblast interactions to enable efficient quorum sensing-driven regeneration. This study provides mechanistic insights into fractional laser-induced tissue regeneration and underscores its potential as a minimally invasive therapeutic strategy for alopecic disorders. Targeting HGF/SF-c-Met signaling pathways offers a promising avenue to enhance regenerative outcomes and optimize laser-based clinical interventions. CHIH-CHIANG CHEN^{1, 2}, Cheng Ming Chuong³ 1. Dermatology, Taipei Veterans General Hospital, Taipei City, Taipei City, Taiwan. 2. Dermatology, National Yang Ming Chiao Tung University, Taipei City, Taiwan. 3. Pathology, University of Southern California, Los Angeles, CA, United States. Stem Cell Biology, Tissue Regeneration and Wound Healing