Gli2-serpinh1 drives fibroblast state transition during skin wound healing
4 affiliations
- 1Key Laboratory of Biorheological Science and Technology of Ministry of Education & 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China
- 2Beijing Anzhen Nanchong Hospital of Capital Medical University & Nanchong Central Hospital, Nanchong, China
- 3The Affiliated Hospital of Beihua University, Jilin, China
- 4Institute of Burn Research, Southwest Hospital, State Key Lab of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Third Military Medical University, Chongqing, China
Abstract
Dermal fibroblasts exhibit spatiotemporal heterogeneity, transitioning from coordinating immune signaling and depositing a provisional extracellular matrix during the early inflammatory phase to driving directional migration and mature matrix synthesis in the proliferative phase of wound healing. However, the molecular mechanisms underlying these fibroblast state transitions remain unclear. Here, by integrating single-cell RNA-sequencing, spatial transcriptomics, and in vivo and in vitro analyses in both mouse and skin organoid models for functional validation, we identify a previously underappreciated Gli2–Serpinh1 regulatory axis that plays a key role in fibroblast state transitions during skin wound healing. Serpinh1⁺ fibroblast subsets drive wound closure through re-epithelialization, vascular regeneration, and actin-mediated filopodia formation. Gli2, as a key upstream regulator of Serpinh1, modulates fibroblast function in a level-dependent manner across different healing states. Leveraging organoid technology as a drug discovery platform, we further identify three traditional Chinese medicine candidates that enhance wound healing by activating the Gli2–Serpinh1 axis. Our study reveals the Gli2–Serpinih1 axis as a pivotal regulator of fibroblast state transitions, providing mechanistic insight into fibroblast heterogeneity during wound healing and opening new avenues for precision regenerative therapies.
Related
- MIF-mediated intercellular crosstalk drives antigen-presenting-like cancer-associated fibroblast differentiation in triple-negative breast cancer via TGF-β signaling
- PDIM drives the transition from repairable to catastrophic EsxA-mediated vacuole membrane damage during Mycobacterium marinum infection
- Wuguchong Bioactive Peptides Promote Wound Healing via Hedgehog Pathway‑Mediated Fibroblast Modulation.
- FAM45A-Mediated Persistent Memory-Like Fibroblast Reprogramming Drives PM2.5-Exacerbated Allergic Asthma
- Ameliorative Effect of a Chenopodium formosanum-Derived Peptide on Diabetic Wound Healing and Fibroblast Dysfunction
BibTeX
@article{ma2026gli2serpinh1,
title = {{Gli2-serpinh1 drives fibroblast state transition during skin wound healing}},
author = {Rui Ma and Wang Wu and Chuqing Zhou and Zeming Li and Jiajun Tan and Jingwei Jiang and Yiping Zhao and Mengyue Wang and Yuanli Ye and Siyi Zhou and Xudong Qiu and Fanbin Meng and Xiao Xiang and Mingxing Lei},
journal = {NPJ Regenerative Medicine},
year = {2026},
month = jul,
doi = {10.1038/s41536-026-00483-w},
url = {https://doi.org/10.1038/s41536-026-00483-w},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Gli2-serpinh1 drives fibroblast state transition during skin wound healing
AU - Rui Ma
AU - Wang Wu
AU - Chuqing Zhou
AU - Zeming Li
AU - Jiajun Tan
AU - Jingwei Jiang
AU - Yiping Zhao
AU - Mengyue Wang
AU - Yuanli Ye
AU - Siyi Zhou
AU - Xudong Qiu
AU - Fanbin Meng
AU - Xiao Xiang
AU - Mingxing Lei
PY - 2026
DA - 2026/07/14
JO - NPJ Regenerative Medicine
DO - 10.1038/s41536-026-00483-w
UR - https://doi.org/10.1038/s41536-026-00483-w
AB - Dermal fibroblasts exhibit spatiotemporal heterogeneity, transitioning from coordinating immune signaling and depositing a provisional extracellular matrix during the early inflammatory phase to driving directional migration and mature matrix synthesis in the proliferative phase of wound healing. However, the molecular mechanisms underlying these fibroblast state transitions remain unclear. Here, by integrating single-cell RNA-sequencing, spatial transcriptomics, and in vivo and in vitro analyses in both mouse and skin organoid models for functional validation, we identify a previously underappreciated Gli2–Serpinh1 regulatory axis that plays a key role in fibroblast state transitions during skin wound healing. Serpinh1⁺ fibroblast subsets drive wound closure through re-epithelialization, vascular regeneration, and actin-mediated filopodia formation. Gli2, as a key upstream regulator of Serpinh1, modulates fibroblast function in a level-dependent manner across different healing states. Leveraging organoid technology as a drug discovery platform, we further identify three traditional Chinese medicine candidates that enhance wound healing by activating the Gli2–Serpinh1 axis. Our study reveals the Gli2–Serpinih1 axis as a pivotal regulator of fibroblast state transitions, providing mechanistic insight into fibroblast heterogeneity during wound healing and opening new avenues for precision regenerative therapies.
SN - 2057-3995
ER -