Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights
Abstract Decompensated liver cirrhosis (DLC) is characterized by severe liver dysfunction and immune dysregulation, posing significant treatment challenges. Mesenchymal stromal cell (MSC) therapy has shown promise in DLC treatment, but the optimal dosing strategies and dose-dependent therapeutic mec...
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Nature Publishing Group
2025-07-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02318-4 |
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| author | Lei Shi Ziying Zhang Song Mei Zerui Wang Zhe Xu Weiqi Yao Limin Liu Mengqi Yuan Yuefei Pan Kaidi Zhu Kai Liu Fanglin Meng Jiao Sun Wenying Liu Xiaohui Xie Tengyun Dong Lei Huang Fanping Meng Jun-Liang Fu Yuanyuan Li Chao Zhang Xing Fan Ming Shi Yu Zhang Yonggang Li Wei-Fen Xie Peng Zhang Fu-Sheng Wang |
| author_facet | Lei Shi Ziying Zhang Song Mei Zerui Wang Zhe Xu Weiqi Yao Limin Liu Mengqi Yuan Yuefei Pan Kaidi Zhu Kai Liu Fanglin Meng Jiao Sun Wenying Liu Xiaohui Xie Tengyun Dong Lei Huang Fanping Meng Jun-Liang Fu Yuanyuan Li Chao Zhang Xing Fan Ming Shi Yu Zhang Yonggang Li Wei-Fen Xie Peng Zhang Fu-Sheng Wang |
| author_sort | Lei Shi |
| collection | DOAJ |
| description | Abstract Decompensated liver cirrhosis (DLC) is characterized by severe liver dysfunction and immune dysregulation, posing significant treatment challenges. Mesenchymal stromal cell (MSC) therapy has shown promise in DLC treatment, but the optimal dosing strategies and dose-dependent therapeutic mechanisms in humans remain unclear, limiting its clinical application. We conducted sequential Phase Ia/Ib trials using a single-arm, dose-escalation design to evaluate the safety and tolerability of MSC therapy in DLC patients while also exploring its immunomodulatory effects and gathering preliminary therapeutic signals. In Phase Ia, four dose cohorts received a single dose of MSCs: 5.0 × 10⁷, 1.0 × 10⁸, 1.5 × 10⁸, and 2.0 × 10⁸ cells. Patients were followed up on Days 3, 7, 14, and 28. Multiomics analyses, including single-cell RNA sequencing and cytometry by time of flight, were conducted to perform exploratory mechanistic analyses investigating immune cell dynamics and dose-dependent responses. Building on these findings, Phase Ib included two dose cohorts, each of which received three doses of MSCs administered one week apart: 1.0 × 10⁸ and 2.0 × 10⁸ cells per dose. Patients were followed up on Days 7, 14, 21, and 28 to further evaluate the safety and feasibility of multiple-dose regimens. The trials were registered at ClinicalTrials.gov (NCT05227846 and NCT05984303). MSC therapy demonstrated good safety and tolerability in both Phase Ia and Phase Ib trials, with no severe adverse events, dose-limiting toxicities, or serious unexpected adverse reactions observed up to Day 28. Multi-omics analyses revealed that higher MSC doses elicited stronger immunomodulatory effects, particularly by modulating monocyte subsets. In particular, myxovirus resistance 1 positive (MX1+) monocytes, a key monocyte population, exhibited dose-dependent changes and were identified as a mediator of MSC-induced immunomodulation. These effects were sustained for up to seven days post-treatment but diminished by Day 14. Preliminary clinical signals included improvements in Child–Pugh scores, Model for End-Stage Liver Disease scores, liver function markers, and quality-of-life metrics, particularly in the higher-dose and multiple-dose groups. This study demonstrates the safety and tolerability of MSC therapy in patients with DLC and provides the first human-based evidence on the dose‒effect relationship and optimal administration regimens. The identification of MX1+ monocytes as a critical mediator highlights the potential of MSC therapy to modulate immune dysfunction in DLC. These findings offer valuable insights for optimizing MSC therapy and informing the design of future efficacy-focused clinical trials. |
| format | Article |
| id | doaj-art-4cebd697736640a991cc996cfd195b30 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
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| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-4cebd697736640a991cc996cfd195b302025-08-20T03:43:37ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-07-0110111610.1038/s41392-025-02318-4Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insightsLei Shi0Ziying Zhang1Song Mei2Zerui Wang3Zhe Xu4Weiqi Yao5Limin Liu6Mengqi Yuan7Yuefei Pan8Kaidi Zhu9Kai Liu10Fanglin Meng11Jiao Sun12Wenying Liu13Xiaohui Xie14Tengyun Dong15Lei Huang16Fanping Meng17Jun-Liang Fu18Yuanyuan Li19Chao Zhang20Xing Fan21Ming Shi22Yu Zhang23Yonggang Li24Wei-Fen Xie25Peng Zhang26Fu-Sheng Wang27Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesBeijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children; Rare Disease Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthSenior Department of Gastroenterology, the First Medical Center of Chinese PLA General HospitalSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSchool of Life and Health Sciences, Hubei University of TechnologySenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesWuhan Optics Valley Zhongyuan Pharmaceutical Co., Ltd.Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesWuhan Optics Valley Zhongyuan Pharmaceutical Co., Ltd.Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesDepartment of Gastroenterology, Changzheng Hospital, Second Military Medical UniversityBeijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children; Rare Disease Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthSenior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious DiseasesAbstract Decompensated liver cirrhosis (DLC) is characterized by severe liver dysfunction and immune dysregulation, posing significant treatment challenges. Mesenchymal stromal cell (MSC) therapy has shown promise in DLC treatment, but the optimal dosing strategies and dose-dependent therapeutic mechanisms in humans remain unclear, limiting its clinical application. We conducted sequential Phase Ia/Ib trials using a single-arm, dose-escalation design to evaluate the safety and tolerability of MSC therapy in DLC patients while also exploring its immunomodulatory effects and gathering preliminary therapeutic signals. In Phase Ia, four dose cohorts received a single dose of MSCs: 5.0 × 10⁷, 1.0 × 10⁸, 1.5 × 10⁸, and 2.0 × 10⁸ cells. Patients were followed up on Days 3, 7, 14, and 28. Multiomics analyses, including single-cell RNA sequencing and cytometry by time of flight, were conducted to perform exploratory mechanistic analyses investigating immune cell dynamics and dose-dependent responses. Building on these findings, Phase Ib included two dose cohorts, each of which received three doses of MSCs administered one week apart: 1.0 × 10⁸ and 2.0 × 10⁸ cells per dose. Patients were followed up on Days 7, 14, 21, and 28 to further evaluate the safety and feasibility of multiple-dose regimens. The trials were registered at ClinicalTrials.gov (NCT05227846 and NCT05984303). MSC therapy demonstrated good safety and tolerability in both Phase Ia and Phase Ib trials, with no severe adverse events, dose-limiting toxicities, or serious unexpected adverse reactions observed up to Day 28. Multi-omics analyses revealed that higher MSC doses elicited stronger immunomodulatory effects, particularly by modulating monocyte subsets. In particular, myxovirus resistance 1 positive (MX1+) monocytes, a key monocyte population, exhibited dose-dependent changes and were identified as a mediator of MSC-induced immunomodulation. These effects were sustained for up to seven days post-treatment but diminished by Day 14. Preliminary clinical signals included improvements in Child–Pugh scores, Model for End-Stage Liver Disease scores, liver function markers, and quality-of-life metrics, particularly in the higher-dose and multiple-dose groups. This study demonstrates the safety and tolerability of MSC therapy in patients with DLC and provides the first human-based evidence on the dose‒effect relationship and optimal administration regimens. The identification of MX1+ monocytes as a critical mediator highlights the potential of MSC therapy to modulate immune dysfunction in DLC. These findings offer valuable insights for optimizing MSC therapy and informing the design of future efficacy-focused clinical trials.https://doi.org/10.1038/s41392-025-02318-4 |
| spellingShingle | Lei Shi Ziying Zhang Song Mei Zerui Wang Zhe Xu Weiqi Yao Limin Liu Mengqi Yuan Yuefei Pan Kaidi Zhu Kai Liu Fanglin Meng Jiao Sun Wenying Liu Xiaohui Xie Tengyun Dong Lei Huang Fanping Meng Jun-Liang Fu Yuanyuan Li Chao Zhang Xing Fan Ming Shi Yu Zhang Yonggang Li Wei-Fen Xie Peng Zhang Fu-Sheng Wang Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights Signal Transduction and Targeted Therapy |
| title | Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights |
| title_full | Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights |
| title_fullStr | Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights |
| title_full_unstemmed | Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights |
| title_short | Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights |
| title_sort | dose escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis phase ia ib results and immune modulation insights |
| url | https://doi.org/10.1038/s41392-025-02318-4 |
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