Astrocyte Secretome Profiling via Biorthogonal Labeling Unveils Novel Factors Relevant to Neurodegenerative Diseases
Secreted proteins are key mediators of intercellular communication in multicellular organisms. However, progress in secretomics has been hindered by the lack of effective methods for capturing secreted proteins. Here, we present a two-step secretome enrichment method (tsSEM) that integrates unnatural amino acid labeling with click chemistry-based biorthogonal reaction, enabling robust in vitro secretome profiling in the presence of serum. Applying tsSEM, we systematically analyzed the secretome of human induced pluripotent stem cells (iPSCs)-derived astrocytes (iAst) across various disease models and identified a panel of astrocyte-secreted proteins contributing to noncell autonomous neurotoxicity. Among these, we validated two novel neurotrophic factors, FAM3C and KITLG, which enhanced neurite outgrowth, protected neuronal viability, and promoted neural progenitor proliferation. Our findings demonstrate the utility of tsSEM for high-resolution secretome analysis and underscore the potential of iAst-derived secretomes in elucidating disease mechanisms and identifying therapeutic targets.
Authors
- Gang Pei (ORCID: https://orcid.org/0000-0001-5517-8496)
- Jia He (ORCID: https://orcid.org/0000-0002-6195-1462)
- Yaoyang Zhang (ORCID: https://orcid.org/0000-0001-5363-9834)
- Jie Liu (ORCID: https://orcid.org/0000-0002-5844-7900)
- Liu‐Lin Xiong (ORCID: https://orcid.org/0000-0002-1623-5969)
- Congcong Xia
- Jian Zhao (ORCID: https://orcid.org/0000-0002-8862-0591)
- Jianxing He (ORCID: https://orcid.org/0000-0003-1737-8192)
- Yi Wu (ORCID: https://orcid.org/0000-0002-4172-9864)
- Lin Guo (ORCID: https://orcid.org/0000-0001-5801-7022)
- Jing Gao (ORCID: https://orcid.org/0000-0002-2036-0658)
- Changyin Yu (ORCID: https://orcid.org/0000-0002-4529-9750)
- Yufang Yang (ORCID: https://orcid.org/0000-0003-0774-8938)
- Guoming Ma
- Mingfeng Guan
- Wenyuan Wang (ORCID: https://orcid.org/0000-0002-8589-8344)
Institutions
- Zunyi Medical University (CN)
- Kunming Institute of Zoology (CN)
- Fudan University (CN)
- Kunming Medical University (CN)
- ShanghaiTech University (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Center for Excellence in Molecular Cell Science (CN)
- Shanghai East Hospital (CN)
- Huashan Hospital (CN)
- Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Glia
- Published
- 2025-08-19
- DOI
- https://doi.org/10.1002/glia.70079
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Key Research and Development Program of China