Clinical research progress and translational challenges of mesenchymal stem cell therapy for acute-on-chronic liver failure_West China Medical Journal

Authors：

AN Shumei ,  LEI Xuezhong

Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding?author：

LEI Xuezhong, Email: 18980601317@163.com

Keywords：

Acute-on-chronic liver failure; mesenchymal stem cell; immunomodulation; cell therapy

DOI：

10.7507/1002-0179.202512285

Video：

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Acute-on-chronic liver failure (ACLF) is a critical illness with high mortality, and current therapeutic approaches still have certain limitations. In recent years, mesenchymal stem cells (MSCs) have attracted extensive attention in the treatment of ACLF owing to their properties including immunomodulation, anti-inflammation and tissue repair. This article reviews the research progress of MSC therapy for ACLF, with emphasis on its mechanisms of action, clinical applications of MSCs from different sources, combination therapeutic strategies, and safety profiles. It also analyzes the problems and challenges in clinical translation and outlines future research directions, so as to provide a relatively comprehensive reference for basic research and clinical application of MSCs in ACLF treatment.

Citation： AN Shumei, LEI Xuezhong. Clinical research progress and translational challenges of mesenchymal stem cell therapy for acute-on-chronic liver failure. West China Medical Journal, 2026, 41(9): 1549-1553. doi: 10.7507/1002-0179.202512285 Copy

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2.	Arroyo V, Moreau R, Kamath PS, et al. Acute-on-chronic liver failure in cirrhosis[J]. Nat Rev Dis Primers, 2016, 2: 16041.
3.	Choi S, Jeong J. Mesenchymal stromal/stem cell-based therapies for liver regeneration: current status and future directions[J]. Int J Mol Sci, 2026, 27(2): 619.
4.	Shi M, Zhang Z, Xu R, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients[J]. Stem Cells Transl Med, 2012, 1(10): 725-731.
5.	Cui L, Zou H, You S, et al. Off-the-shelf human umbilical cord mesenchymal stromal cell product in acute-on-chronic liver failure: a multicenter phase I/II clinical trial[J]. Chin Med J (Engl), 2025, 138(18): 2347-2349.
6.	Lin BL, Chen JF, Qiu WH, et al. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: a randomized controlled trial[J]. Hepatology, 2017, 66(1): 209-219.
7.	Schacher FC, Martins Pezzi da Silva A, Silla LMDR, et al. Bone marrow mesenchymal stem cells in acute-on-chronic liver failure grades 2 and 3: a phase I-II randomized clinical trial[J]. Can J Gastroenterol Hepatol, 2021, 2021: 3662776.
8.	Br VK, Sarin SK. Acute-on-chronic liver failure: terminology, mechanisms and management[J]. Clin Mol Hepatol, 2023, 29(3): 670-689.
9.	Rodríguez-Negrete EV, Gálvez-Martínez M, Sánchez-Reyes K, et al. Liver cirrhosis: the immunocompromised state[J]. J Clin Med, 2024, 13(18): 5582.
10.	Hu C, Wu Z, Li L. Mesenchymal stromal cells promote liver regeneration through regulation of immune cells[J]. Int J Biol Sci, 2020, 16(5): 893-903.
11.	Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged[J]. Nat Biotechnol, 2014, 32(3): 252-260.
12.	Tao Y, Wang Y, Wang M, et al. Mesenchymal stem cells alleviate acute liver failure through regulating hepatocyte apoptosis and macrophage polarization[J]. J Clin Transl Hepatol, 2024, 12(6): 571-580.
13.	Zhang ZH, Zhu W, Ren HZ, et al. Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure[J]. Stem Cell Res Ther, 2017, 8(1): 70.
14.	Xuan J, Feng W, An ZT, et al. Anti-TGFβ-1 receptor inhibitor mediates the efficacy of the human umbilical cord mesenchymal stem cells against liver fibrosis through TGFβ-1/Smad pathway[J]. Mol Cell Biochem, 2017, 429(1-2): 113-122.
15.	Zhang J, Gao J, Li X, et al. Bone marrow mesenchymal stem cell-derived small extracellular vesicles promote liver regeneration via miR-20a-5p/PTEN[J]. Front Pharmacol, 2023, 14: 1168545.
16.	Lin S, Gao H, Ma H, et al. A comprehensive meta-analysis of stem cell therapy for liver failure: assessing treatment efficacy and modality[J]. Ann Hepatol, 2025, 30(2): 101586.
17.	Phinney DG, Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views[J]. Stem Cells, 2007, 25(11): 2896-2902.
18.	Jin HJ, Bae YK, Kim M, et al. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy[J]. Int J Mol Sci, 2013, 14(9): 17986-18001.
19.	Sakai Y, Takamura M, Seki A, et al. Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell[J]. Regen Ther, 2017, 6: 52-64.
20.	陳曦, 陳照林, 董靜, 等. 臍帶間充質干細胞聯合雙重血漿分子吸附治療慢加急性肝衰竭患者臨床效果初步觀察[J]. 實用肝臟病雜志, 2020, 23(4): 544-547.
21.	Li YH, Xu Y, Wu HM, et al. Umbilical cord-derived mesenchymal stem cell transplantation in hepatitis B virus related acute-on-chronic liver failure treated with plasma exchange and entecavir: a 24-month prospective study[J]. Stem Cell Rev Rep, 2016, 12(6): 645-653.
22.	Xu WX, He HL, Pan SW, et al. Combination treatments of plasma exchange and umbilical cord-derived mesenchymal stem cell transplantation for patients with hepatitis B virus-related acute-on-chronic liver failure: a clinical trial in China[J]. Stem Cells Int, 2019, 2019: 4130757.
23.	Lin D, Chen H, Xiong J, et al. Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB[J]. Cell Death Dis, 2022, 13(10): 865.
24.	Kukaj D, Niebert S, Biehl C, et al. No simple way to averaging out: pooled mesenchymal stromal cells do not reflect average donor characteristics[J]. Regen Ther, 2025, 30: 849-859.
25.	Mayeen NF, Salma U, Abu Kasim NH, et al. Hurdles to overcome for mesenchymal stem cell translation from bench to bedside[J]. World J Stem Cells, 2025, 17(12): 114349.
26.	Ferrini E, Stellari FF, Franceschi V, et al. Persistency of mesenchymal stromal/stem cells in lungs[J]. Front Cell Dev Biol, 2021, 9: 709225.
27.	Yuan M, Hu X, Yao L, et al. Mesenchymal stem cell homing to improve therapeutic efficacy in liver disease[J]. Stem Cell Res Ther, 2022, 13(1): 179.
28.	Li TT, Wang ZR, Yao WQ, et al. Stem cell therapies for chronic liver diseases: progress and challenges[J]. Stem Cells Transl Med, 2022, 11(9): 900-911.
29.	Leonov GE, Grinchevskaya LR, Makhnach OV, et al. Safety assessment of stem cell-based therapies: current standards and advancing frameworks[J]. Cells, 2025, 14(21): 1660.

1. Trebicka J, Praktiknjo M, Peiffer KH, et al. Acute-on-chronic liver failure[J]. Dtsch Arztebl Int, 2025, 122(4): 96-102.
2. Arroyo V, Moreau R, Kamath PS, et al. Acute-on-chronic liver failure in cirrhosis[J]. Nat Rev Dis Primers, 2016, 2: 16041.
3. Choi S, Jeong J. Mesenchymal stromal/stem cell-based therapies for liver regeneration: current status and future directions[J]. Int J Mol Sci, 2026, 27(2): 619.
4. Shi M, Zhang Z, Xu R, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients[J]. Stem Cells Transl Med, 2012, 1(10): 725-731.
5. Cui L, Zou H, You S, et al. Off-the-shelf human umbilical cord mesenchymal stromal cell product in acute-on-chronic liver failure: a multicenter phase I/II clinical trial[J]. Chin Med J (Engl), 2025, 138(18): 2347-2349.
6. Lin BL, Chen JF, Qiu WH, et al. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: a randomized controlled trial[J]. Hepatology, 2017, 66(1): 209-219.
7. Schacher FC, Martins Pezzi da Silva A, Silla LMDR, et al. Bone marrow mesenchymal stem cells in acute-on-chronic liver failure grades 2 and 3: a phase I-II randomized clinical trial[J]. Can J Gastroenterol Hepatol, 2021, 2021: 3662776.
8. Br VK, Sarin SK. Acute-on-chronic liver failure: terminology, mechanisms and management[J]. Clin Mol Hepatol, 2023, 29(3): 670-689.
9. Rodríguez-Negrete EV, Gálvez-Martínez M, Sánchez-Reyes K, et al. Liver cirrhosis: the immunocompromised state[J]. J Clin Med, 2024, 13(18): 5582.
10. Hu C, Wu Z, Li L. Mesenchymal stromal cells promote liver regeneration through regulation of immune cells[J]. Int J Biol Sci, 2020, 16(5): 893-903.
11. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged[J]. Nat Biotechnol, 2014, 32(3): 252-260.
12. Tao Y, Wang Y, Wang M, et al. Mesenchymal stem cells alleviate acute liver failure through regulating hepatocyte apoptosis and macrophage polarization[J]. J Clin Transl Hepatol, 2024, 12(6): 571-580.
13. Zhang ZH, Zhu W, Ren HZ, et al. Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure[J]. Stem Cell Res Ther, 2017, 8(1): 70.
14. Xuan J, Feng W, An ZT, et al. Anti-TGFβ-1 receptor inhibitor mediates the efficacy of the human umbilical cord mesenchymal stem cells against liver fibrosis through TGFβ-1/Smad pathway[J]. Mol Cell Biochem, 2017, 429(1-2): 113-122.
15. Zhang J, Gao J, Li X, et al. Bone marrow mesenchymal stem cell-derived small extracellular vesicles promote liver regeneration via miR-20a-5p/PTEN[J]. Front Pharmacol, 2023, 14: 1168545.
16. Lin S, Gao H, Ma H, et al. A comprehensive meta-analysis of stem cell therapy for liver failure: assessing treatment efficacy and modality[J]. Ann Hepatol, 2025, 30(2): 101586.
17. Phinney DG, Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views[J]. Stem Cells, 2007, 25(11): 2896-2902.
18. Jin HJ, Bae YK, Kim M, et al. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy[J]. Int J Mol Sci, 2013, 14(9): 17986-18001.
19. Sakai Y, Takamura M, Seki A, et al. Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell[J]. Regen Ther, 2017, 6: 52-64.
20. 陳曦, 陳照林, 董靜, 等. 臍帶間充質干細胞聯合雙重血漿分子吸附治療慢加急性肝衰竭患者臨床效果初步觀察[J]. 實用肝臟病雜志, 2020, 23(4): 544-547.
21. Li YH, Xu Y, Wu HM, et al. Umbilical cord-derived mesenchymal stem cell transplantation in hepatitis B virus related acute-on-chronic liver failure treated with plasma exchange and entecavir: a 24-month prospective study[J]. Stem Cell Rev Rep, 2016, 12(6): 645-653.
22. Xu WX, He HL, Pan SW, et al. Combination treatments of plasma exchange and umbilical cord-derived mesenchymal stem cell transplantation for patients with hepatitis B virus-related acute-on-chronic liver failure: a clinical trial in China[J]. Stem Cells Int, 2019, 2019: 4130757.
23. Lin D, Chen H, Xiong J, et al. Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB[J]. Cell Death Dis, 2022, 13(10): 865.
24. Kukaj D, Niebert S, Biehl C, et al. No simple way to averaging out: pooled mesenchymal stromal cells do not reflect average donor characteristics[J]. Regen Ther, 2025, 30: 849-859.
25. Mayeen NF, Salma U, Abu Kasim NH, et al. Hurdles to overcome for mesenchymal stem cell translation from bench to bedside[J]. World J Stem Cells, 2025, 17(12): 114349.
26. Ferrini E, Stellari FF, Franceschi V, et al. Persistency of mesenchymal stromal/stem cells in lungs[J]. Front Cell Dev Biol, 2021, 9: 709225.
27. Yuan M, Hu X, Yao L, et al. Mesenchymal stem cell homing to improve therapeutic efficacy in liver disease[J]. Stem Cell Res Ther, 2022, 13(1): 179.
28. Li TT, Wang ZR, Yao WQ, et al. Stem cell therapies for chronic liver diseases: progress and challenges[J]. Stem Cells Transl Med, 2022, 11(9): 900-911.
29. Leonov GE, Grinchevskaya LR, Makhnach OV, et al. Safety assessment of stem cell-based therapies: current standards and advancing frameworks[J]. Cells, 2025, 14(21): 1660.

West China Medical Journal

Clinical research progress and translational challenges of mesenchymal stem cell therapy for acute-on-chronic liver failure

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