TGF-β signaling-mediated wound healing is required for hair follicle neogenesis

Summary: Abstract Body: Mammalian adult skin wounds typically end in fibrosis and fail to regenerate skin appendages, such as hair follicles (HFs). Our previous studies demonstrated that new HFs regenerate in the center of large full-thickness wounds of mice following wound healing. However, it remains unclear how the initial wound healing mechanisms are linked to the later HF neogenesis (HFN). Transforming growth factor-β (TGF-β) is a pivotal mediator in wound healing, promoting myofibroblast differentiation and extracellular matrix deposition, including collagen, in the wound dermis. We aimed to understand HFN-competent tissue state, specifically focusing on TGF-β signaling-mediated wound healing. Using multiple genetically modified mouse models, we depleted TGF-β signaling to explore its role in wound-induced HFN. Conditional knockout of TGF-β receptor 2 in wound fibroblasts before but not after re-epithelialization inhibited HFN and reduced myofibroblast differentiation and collagen deposition. These results suggest that TGF-β signaling during wound healing is critical for HFN. Further, conditional knockout of collagen type I in wound fibroblasts also inhibited HFN, which was rescued by the activation of the Sonic hedgehog (Shh) signaling. Spatial transcriptomic analysis further revealed that the absence of TGF-β signaling disrupted macrophage infiltration and chemoattractant expression, major players in wound healing and HFN, as well as Shh signaling activation in the wound dermis. Collectively, our results suggest that TGF-β signaling orchestrates wound healing process by sufficient collagen deposition and macrophage recruitment in the wound dermis, which may provide the regenerative microenvironment to initiate HFN. Tatsuya Ogawa¹, Chae Ho Lim¹, Hideyuki Kosumi¹, Olivia Yeroushalmi¹, Priya Marella¹, Raaita Anwar¹, Sofia Barlas¹, Annette Kaminaka¹, Soung Hoon Lee¹, Ito Mayumi¹ 1. Dermatology, New York University, New York, NY, United States. Stem Cell Biology, Tissue Regeneration and Wound Healing