Volume 32, Issue 1 (3-2025)
RJMS 2025, 32(1): 1-18 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Moudi B, Karbalaie-Harofteh M, Moudi M. A Review of Stem Cell-based Therapies for Human Liver Diseases. RJMS 2025; 32 (1) :1-18
URL: http://rjms.iums.ac.ir/article-1-7918-en.html
URL: http://rjms.iums.ac.ir/article-1-7918-en.html
Infectious Disease and Tropical Medicine Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran, & Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran , bita.moudi@yahoo.com
Abstract: (1160 Views)
Liver diseases encompassing acute liver failure, cirrhosis, non-alcoholic fatty liver disease (NAFLD), autoimmune hepatitis, and hepatocellular carcinoma (HCC) represent a significant global health burden with high morbidity and mortality. Orthotopic liver transplantation remains the only definitive cure for end-stage liver disease but its utility is severely limited by organ scarcity, surgical complexity and the need for lifelong immunosuppression. This has propelled the search for alternative regenerative therapies among which cell-based approaches particularly using mesenchymal stem cells (MSCs) have emerged as a highly promising strategy.
MSCs are multipotent stromal cells characterized by their self-renewal capacity, multi-lineage differentiation potential, and potent immunomodulatory properties. They can be readily isolated from various tissues, including bone marrow (BM-MSCs), adipose tissue, and, most notably for clinical applications, the umbilical cord (UC-MSCs). Their appeal lies in their low immunogenicity owing to minimal expression of major histocompatibility complex class II molecules, which facilitates allogeneic transplantation without rigorous matching. The therapeutic mechanisms of MSCs in liver repair are multifaceted and extend beyond the initial hope of direct transdifferentiation into functional hepatocytes. While in vitro studies show that MSCs can be induced to differentiate into hepatocyte-like cells (HLCs) using specific growth factors (HGF, EGF, FGF, OSM), the in vivo contribution of this process to functional recovery is considered minimal. Instead, the primary therapeutic benefits are attributed to powerful paracrine signaling and immunomodulation. A central mechanism of action is the profound modulation of the immune response. MSCs interact with and regulate both innate and adaptive immune cells. They can polarize pro-inflammatory M1 macrophages towards an anti-inflammatory, tissue-reparative M2 phenotype, partly through prostaglandin E2 (PGE2) secretion. They inhibit the maturation and antigen-presenting function of dendritic cells and directly suppress the proliferation and activation of T and B lymphocytes. Crucially, MSCs promote the expansion of regulatory T cells (Tregs), which are essential for restoring immune homeostasis and mitigating the chronic inflammatory drive that propels fibrosis and disease progression in the liver. Furthermore, MSCs exert potent anti-fibrotic effects. Liver fibrosis results from an imbalance in extracellular matrix (ECM) synthesis and degradation, primarily driven by activated hepatic stellate cells (HSCs). MSCs secrete a plethora of factors, such as HGF and interleukin-10 (IL-10), that directly suppress HSC activation and collagen production. They also promote fibrosis resolution by upregulating matrix metalloproteinases (MMPs like MMP-9 and MMP-13), which degrade excess ECM, and by inhibiting the pro-fibrotic transforming growth factor-beta 1 (TGF-β1)/Smad signaling pathway.
The efficacy of MSC therapy has been extensively demonstrated in preclinical animal models of various liver ailments. In models of acute liver failure (ALF) induced by toxins like acetaminophen, intravenous infusion of UC-MSCs significantly reduces liver injury biomarkers, improves histology, and enhances survival rates, partly by dampening the systemic inflammatory cascade. In chronic models of liver fibrosis and cirrhosis, BM-MSC transplantation has been shown to reduce collagen deposition, hydroxyproline content, and reverse histological signs of fibrosis. In NAFLD models, MSC administration improves lipid and glucose metabolism, reduces hepatic steatosis, insulin resistance, and inflammation, showcasing their potential to address the metabolic underpinnings of the disease. The role of MSCs in HCC is complex and appears to be a "double-edged sword"; while some studies report anti-tumor effects through inhibition of cancer cell proliferation and induction of apoptosis, others suggest they may potentially promote tumor growth by enhancing angiogenesis, highlighting the need for careful evaluation in oncological settings.
Translating these preclinical successes to the clinic, numerous phase I/II clinical trials have been initiated. These studies consistently affirm the safety and feasibility of both autologous and allogeneic MSC transplantation in patients with cirrhosis and acute-on-chronic liver failure (ACLF). Trials using UC-MSCs or BM-MSCs in patients with HBV-related decompensated cirrhosis have reported significant improvements in liver function tests (e.g., albumin, ALT, AST), reduction in ascites volume, and enhanced quality of life. A pivotal randomized controlled trial in patients with HBV-associated ACLF showed that allogeneic BM-MSC infusion significantly improved survival and reduced the incidence of severe infections and organ failure compared to standard medical therapy. While these results are encouraging, most trials note short-to-medium term clinical improvements, with long-term survival benefits not yet conclusively proven. Challenges remain in standardizing optimal cell sources (UC-MSCs may possess advantages over BM-MSCs in proliferation capacity and senescence), dosages, injection routes (peripheral vs. portal), and treatment frequency. In conclusion, MSC-based therapy represents a groundbreaking and safe regenerative approach for a spectrum of liver diseases. Its therapeutic power is rooted not in cell replacement but in the cells' unparalleled capacity to modulate the immune landscape, counteract fibrosis, and promote a pro-regenerative microenvironment through paracrine actions. While current clinical data are promising, larger, well-designed phase III randomized controlled trials with longer follow-up periods are imperative to conclusively establish definitive efficacy, standardize protocols, and fully understand long-term safety profiles, particularly concerning potential pro-tumorigenic effects. Future directions may also focus on the use of MSC-derived exosomes as a novel cell-free therapeutic strategy, offering the benefits of MSC paracrine activity without the risks associated with whole-cell transplantation.
MSCs are multipotent stromal cells characterized by their self-renewal capacity, multi-lineage differentiation potential, and potent immunomodulatory properties. They can be readily isolated from various tissues, including bone marrow (BM-MSCs), adipose tissue, and, most notably for clinical applications, the umbilical cord (UC-MSCs). Their appeal lies in their low immunogenicity owing to minimal expression of major histocompatibility complex class II molecules, which facilitates allogeneic transplantation without rigorous matching. The therapeutic mechanisms of MSCs in liver repair are multifaceted and extend beyond the initial hope of direct transdifferentiation into functional hepatocytes. While in vitro studies show that MSCs can be induced to differentiate into hepatocyte-like cells (HLCs) using specific growth factors (HGF, EGF, FGF, OSM), the in vivo contribution of this process to functional recovery is considered minimal. Instead, the primary therapeutic benefits are attributed to powerful paracrine signaling and immunomodulation. A central mechanism of action is the profound modulation of the immune response. MSCs interact with and regulate both innate and adaptive immune cells. They can polarize pro-inflammatory M1 macrophages towards an anti-inflammatory, tissue-reparative M2 phenotype, partly through prostaglandin E2 (PGE2) secretion. They inhibit the maturation and antigen-presenting function of dendritic cells and directly suppress the proliferation and activation of T and B lymphocytes. Crucially, MSCs promote the expansion of regulatory T cells (Tregs), which are essential for restoring immune homeostasis and mitigating the chronic inflammatory drive that propels fibrosis and disease progression in the liver. Furthermore, MSCs exert potent anti-fibrotic effects. Liver fibrosis results from an imbalance in extracellular matrix (ECM) synthesis and degradation, primarily driven by activated hepatic stellate cells (HSCs). MSCs secrete a plethora of factors, such as HGF and interleukin-10 (IL-10), that directly suppress HSC activation and collagen production. They also promote fibrosis resolution by upregulating matrix metalloproteinases (MMPs like MMP-9 and MMP-13), which degrade excess ECM, and by inhibiting the pro-fibrotic transforming growth factor-beta 1 (TGF-β1)/Smad signaling pathway.
The efficacy of MSC therapy has been extensively demonstrated in preclinical animal models of various liver ailments. In models of acute liver failure (ALF) induced by toxins like acetaminophen, intravenous infusion of UC-MSCs significantly reduces liver injury biomarkers, improves histology, and enhances survival rates, partly by dampening the systemic inflammatory cascade. In chronic models of liver fibrosis and cirrhosis, BM-MSC transplantation has been shown to reduce collagen deposition, hydroxyproline content, and reverse histological signs of fibrosis. In NAFLD models, MSC administration improves lipid and glucose metabolism, reduces hepatic steatosis, insulin resistance, and inflammation, showcasing their potential to address the metabolic underpinnings of the disease. The role of MSCs in HCC is complex and appears to be a "double-edged sword"; while some studies report anti-tumor effects through inhibition of cancer cell proliferation and induction of apoptosis, others suggest they may potentially promote tumor growth by enhancing angiogenesis, highlighting the need for careful evaluation in oncological settings.
Translating these preclinical successes to the clinic, numerous phase I/II clinical trials have been initiated. These studies consistently affirm the safety and feasibility of both autologous and allogeneic MSC transplantation in patients with cirrhosis and acute-on-chronic liver failure (ACLF). Trials using UC-MSCs or BM-MSCs in patients with HBV-related decompensated cirrhosis have reported significant improvements in liver function tests (e.g., albumin, ALT, AST), reduction in ascites volume, and enhanced quality of life. A pivotal randomized controlled trial in patients with HBV-associated ACLF showed that allogeneic BM-MSC infusion significantly improved survival and reduced the incidence of severe infections and organ failure compared to standard medical therapy. While these results are encouraging, most trials note short-to-medium term clinical improvements, with long-term survival benefits not yet conclusively proven. Challenges remain in standardizing optimal cell sources (UC-MSCs may possess advantages over BM-MSCs in proliferation capacity and senescence), dosages, injection routes (peripheral vs. portal), and treatment frequency. In conclusion, MSC-based therapy represents a groundbreaking and safe regenerative approach for a spectrum of liver diseases. Its therapeutic power is rooted not in cell replacement but in the cells' unparalleled capacity to modulate the immune landscape, counteract fibrosis, and promote a pro-regenerative microenvironment through paracrine actions. While current clinical data are promising, larger, well-designed phase III randomized controlled trials with longer follow-up periods are imperative to conclusively establish definitive efficacy, standardize protocols, and fully understand long-term safety profiles, particularly concerning potential pro-tumorigenic effects. Future directions may also focus on the use of MSC-derived exosomes as a novel cell-free therapeutic strategy, offering the benefits of MSC paracrine activity without the risks associated with whole-cell transplantation.
Type of Study: review article |
Subject:
Biology
Send email to the article author
