Human pluripotent stem cell-derived skin organoids enabled pathophysiological model of Mycobacterium tuberculosis infection
Cutaneous tuberculosis (CTB) is an infectious disease highly associated with extracellular matrix remodeling and granuloma-driven fibrosis. Fibroblasts play crucial roles in this fibrotic process, but their specific roles in Mycobacterium tuberculosis (Mtb) skin infections remain unclear due to the lack of proper in vitro models. Here, we demonstrate that skin organoids (SKOs) derived from human induced pluripotent stem cells can model CTB infected by Mtb. Single-cell RNA analyses reveal an increase in fibroblasts, upregulation of genes involved in collagen synthesis, and enhanced collagen degradation induced by MMP2 and MMP14 in Mtb-infected SKOs. This is accompanied by the destruction of nerve cells and adipocytes. Importantly, the onset of fibrosis in Mtb-infected SKOs is dependent on the activation of the PI3K-AKT signaling pathway and transcription factor AP1 in fibroblasts. Pharmacological inhibition of PI3K-AKT and AP1 alleviates fibrosis and collagen deposition. Our findings have uncovered distinct alterations in cell populations during Mtb-induced skin fibrosis, highlighting the crucial roles of PI3K-AKT and AP1. The study demonstrates the utility of SKOs for investigating CTB pathogenesis and evaluating potential antifibrotic treatments.
Authors
- Leixin Ge
- Yue Liang (ORCID: https://orcid.org/0000-0002-5925-6743)
- Li Fang (ORCID: https://orcid.org/0009-0005-7520-6999)
- Xiaochen Bo (ORCID: https://orcid.org/0000-0003-1911-7922)
- Meida Xiang
- Hebing Chen (ORCID: https://orcid.org/0000-0003-4102-356X)
- Zhimin Yun
- Xiaochen Qiu (ORCID: https://orcid.org/0009-0001-5842-7643)
- Jiru Wang (ORCID: https://orcid.org/0000-0002-7053-3801)
- Qisheng Su (ORCID: https://orcid.org/0000-0003-3858-1018)
- Jie Zhang (ORCID: https://orcid.org/0000-0002-0466-2955)
- Yating Liang (ORCID: https://orcid.org/0009-0005-0637-5748)
- Ying‐Xia Tan (ORCID: https://orcid.org/0000-0003-3729-3786)
- Chaofan Li (ORCID: https://orcid.org/0000-0002-5426-1498)
- Pengfei Zhong (ORCID: https://orcid.org/0009-0001-6021-2625)
- Chengjun Wu (ORCID: https://orcid.org/0000-0001-9940-2605)
Institutions
- Qingdao University (CN)
- Hebei North University (CN)
- Dalian University of Technology (CN)
- Academy of Military Medical Sciences (CN)
- Chinese PLA General Hospital (CN)
- Dalian University (CN)
- Second Hospital of Shandong University (CN)
- Affiliated Hospital of Qingdao University (CN)
- Qingdao Municipal Hospital (CN)
- National Institute for Radiological Protection (CN)
- Qilu Hospital of Shandong University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-02
- DOI
- https://doi.org/10.1038/s41467-025-65848-z
- Primary Topic
- Dermatology and Skin Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Uppsala Universitet
- National Key Research and Development Program of China