Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights

作者：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, Junliang Fu, Yuanyuan Li, Chao Zhang, Xing Fan, Ming Shi, Yu Zhang, Yonggang Li, Wei‐Fen Xie, Peng Zhang, Fu‐Sheng Wang · 发表于：Signal Transduction and Targeted Therapy · 年份：2025 · DOI：10.1038/s41392-025-02318-4 · 被引用次数：15 · 研究领域：Mesenchymal stem cell research、Liver physiology and pathology、Liver Disease Diagnosis and Treatment

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 adve...