Host FSTL1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophages
Abstract Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies, despite uncertainty about its clinical therapeutic efficacy and unclear underlying mechanisms. Here, we investigated the role of follistatin-like 1 (FSTL1), a profibrotic a...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02162-6 |
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| author | Xiaohong Zheng Siyuan Tian Ting Li Si Zhang Xia Zhou Yansheng Liu Rui Su Miao Zhang Bo Li Chao Qi Guanya Guo Shuoyi Ma Keshuai Sun Fangfang Yang Yinan Hu Chunmei Yang Lina Cui Yulong Shang Changcun Guo Boquan Jin Lei Guan Jingbo Wang Wen Ning Ying Han |
| author_facet | Xiaohong Zheng Siyuan Tian Ting Li Si Zhang Xia Zhou Yansheng Liu Rui Su Miao Zhang Bo Li Chao Qi Guanya Guo Shuoyi Ma Keshuai Sun Fangfang Yang Yinan Hu Chunmei Yang Lina Cui Yulong Shang Changcun Guo Boquan Jin Lei Guan Jingbo Wang Wen Ning Ying Han |
| author_sort | Xiaohong Zheng |
| collection | DOAJ |
| description | Abstract Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies, despite uncertainty about its clinical therapeutic efficacy and unclear underlying mechanisms. Here, we investigated the role of follistatin-like 1 (FSTL1), a profibrotic and proinflammatory matricellular protein, in inflammation-related heterogeneity in stem cell therapy. Our results showed that a high level of circulating FSTL1 is significantly correlated with therapeutic response in patients with cirrhosis. FSTL1 facilitated MSC-mediated early recruitment of Ly6C+ inflammatory macrophages within 24 h postinfusion, which was essential for the empowerment of MSCs and subsequent Ly6C−CX3CR1+ macrophage remodelling at 48 h postinfusion. Fstl1 deficiency abrogated early macrophage recruitment and effective Ly6C−CX3CR1+ macrophage accumulation, resulting in the poor antifibrotic effect of MSCs in mice. Whereas, recombinant FSTL1 protein restored the therapeutic efficacy of MSCs in CCl4-injured Fstl1 +/− mice. Mechanistically, host FSTL1 enhanced rapid recycling of CCR2 to the membrane via activation of the CD14/TLR4/NF-κB/ATP6V1G2 axis, leading to early recruitment of Ly6C+ monocytes /macrophages. Taken together, our findings revealed that FSTL1 is a critical regulator of the fibrotic immune microenvironment and facilitates subsequent stem cell therapy. These data suggest that FSTL1 could serve as a predictive biomarker of stem cell therapy response in patients with liver cirrhosis. |
| format | Article |
| id | doaj-art-402d42e35b164dfebe37b8fac5e5087e |
| institution | DOAJ |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-402d42e35b164dfebe37b8fac5e5087e2025-08-20T02:59:57ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-03-0110111610.1038/s41392-025-02162-6Host FSTL1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophagesXiaohong Zheng0Siyuan Tian1Ting Li2Si Zhang3Xia Zhou4Yansheng Liu5Rui Su6Miao Zhang7Bo Li8Chao Qi9Guanya Guo10Shuoyi Ma11Keshuai Sun12Fangfang Yang13Yinan Hu14Chunmei Yang15Lina Cui16Yulong Shang17Changcun Guo18Boquan Jin19Lei Guan20Jingbo Wang21Wen Ning22Ying Han23Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityDepartment of Immunology, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai UniversityXijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical UniversityAbstract Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies, despite uncertainty about its clinical therapeutic efficacy and unclear underlying mechanisms. Here, we investigated the role of follistatin-like 1 (FSTL1), a profibrotic and proinflammatory matricellular protein, in inflammation-related heterogeneity in stem cell therapy. Our results showed that a high level of circulating FSTL1 is significantly correlated with therapeutic response in patients with cirrhosis. FSTL1 facilitated MSC-mediated early recruitment of Ly6C+ inflammatory macrophages within 24 h postinfusion, which was essential for the empowerment of MSCs and subsequent Ly6C−CX3CR1+ macrophage remodelling at 48 h postinfusion. Fstl1 deficiency abrogated early macrophage recruitment and effective Ly6C−CX3CR1+ macrophage accumulation, resulting in the poor antifibrotic effect of MSCs in mice. Whereas, recombinant FSTL1 protein restored the therapeutic efficacy of MSCs in CCl4-injured Fstl1 +/− mice. Mechanistically, host FSTL1 enhanced rapid recycling of CCR2 to the membrane via activation of the CD14/TLR4/NF-κB/ATP6V1G2 axis, leading to early recruitment of Ly6C+ monocytes /macrophages. Taken together, our findings revealed that FSTL1 is a critical regulator of the fibrotic immune microenvironment and facilitates subsequent stem cell therapy. These data suggest that FSTL1 could serve as a predictive biomarker of stem cell therapy response in patients with liver cirrhosis.https://doi.org/10.1038/s41392-025-02162-6 |
| spellingShingle | Xiaohong Zheng Siyuan Tian Ting Li Si Zhang Xia Zhou Yansheng Liu Rui Su Miao Zhang Bo Li Chao Qi Guanya Guo Shuoyi Ma Keshuai Sun Fangfang Yang Yinan Hu Chunmei Yang Lina Cui Yulong Shang Changcun Guo Boquan Jin Lei Guan Jingbo Wang Wen Ning Ying Han Host FSTL1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophages Signal Transduction and Targeted Therapy |
| title | Host FSTL1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophages |
| title_full | Host FSTL1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophages |
| title_fullStr | Host FSTL1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophages |
| title_full_unstemmed | Host FSTL1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophages |
| title_short | Host FSTL1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophages |
| title_sort | host fstl1 defines the impact of stem cell therapy on liver fibrosis by potentiating the early recruitment of inflammatory macrophages |
| url | https://doi.org/10.1038/s41392-025-02162-6 |
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