• Macrophages
• Mesenchymal stem cells
• Pulmonary fibrosis

• Animals
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/cytology
• Mice
• Umbilical Cord/cytology
• Macrophages/metabolism
• Mesenchymal Stem Cell Transplantation/methods
• Female
• Bleomycin
• Mice, Inbred C57BL
• Humans
• Pulmonary Fibrosis/therapy
• Pulmonary Fibrosis/metabolism
• Pulmonary Fibrosis/pathology
• Pulmonary Fibrosis/chemically induced
• Disease Models, Animal
• Male
• Idiopathic Pulmonary Fibrosis/therapy
• Idiopathic Pulmonary Fibrosis/pathology
• Idiopathic Pulmonary Fibrosis/metabolism

• 20201080606 Tsinghua University Spring Breeze Fund
• 2022Z82WKJ008 Vanke Special Fund for Public Health and Health Discipline Development, Tsinghua University

• CCR2/CCR5 antagonist
• Liver fibrosis
• Liver inflammation
• Matrix metalloproteinase 1
• Monocyte recruitment

• Animals
• Matrix Metalloproteinase 1/metabolism
• Matrix Metalloproteinase 1/genetics
• Mice
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Monocytes/metabolism
• Monocytes/drug effects
• Extracellular Matrix/metabolism
• Hepatic Stellate Cells/metabolism
• Hepatic Stellate Cells/drug effects
• Liver/metabolism
• Liver/pathology
• Liver/drug effects
• Male
• Mice, Inbred C57BL
• Carbon Tetrachloride
• Disease Models, Animal
• Macrophages/metabolism
• Macrophages/drug effects
• Humans
• Cell Movement/drug effects
• Drug Synergism
• Imidazoles
• Sulfoxides

• Bansal Start-up University of Twente
• Juan Rodes Ph.D. Student Fellowship European Association for the Study of the Liver

• Cellular therapy
• Clinical research
• Liver diseases
• Mesenchymal stem cells
• Regenerative medicine

• 2022YFA1105603 National Key R&D Program of China
• 2022YFC2304405 National Key R&D Program of China
• 81900563 National Natural Science Foundation of China
• 20200224 Hangzhou Science and Technology Project
• 2022ZFJH003 Fundamental Research Funds for the Central Universities
• 2019-I2M-5-045 CAMS Innovation Fund for Medical Sciences

The chronic liver diseases will slowly develop into liver fibrosis, cirrhosis, and even liver cancer if no proper control is performed with high efficiency. Up to now, the most effective treatment for end-stage liver diseases is liver transplantation. However, liver transplantation has the problems of donor deficiency, low matching rate, surgical complications, high cost, and immune rejection. These problems indicate that novel therapeutic strategies are urgently required. Mesenchymal stem cells (MSCs) are somatic stem cells with multidirectional differentiation potential and self-renewal ability. MSCs can secrete a large number of cytokines, chemokines, immunomodulatory molecules, and hepatotrophic factors, as well as produce extracellular vesicles. They alleviate liver diseases by differentiating to hepatocyte-like cells, immunomodulation, homing to the injured site, regulating cell ferroptosis, regulating cell autophagy, paracrine effects, and MSC-mitochondrial transfer. In this review, we focus on the main resources of MSCs, underlying therapeutic mechanisms, clinical applications, and efforts made to improve MSC-based cell therapy efficiency.

Recently, mesenchymal stromal cell (MSC)-based therapy has become an appreciated therapeutic approach in the context of neurodegenerative disease therapy. Accordingly, a myriad of studies in animal models and also some clinical trials have evinced the safety, feasibility, and efficacy of MSC transplantation in neurodegenerative conditions, most importantly in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). The MSC-mediated desired effect is mainly a result of secretion of immunomodulatory factors in association with release of various neurotrophic factors (NTFs), such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Thanks to the secretion of protein-degrading molecules, MSC therapy mainly brings about the degradation of pathogenic protein aggregates, which is a typical appearance of chronic neurodegenerative disease. Such molecules, in turn, diminish neuroinflammation and simultaneously enable neuroprotection, thereby alleviating disease pathological symptoms and leading to cognitive and functional recovery. Also, MSC differentiation into neural-like cells in vivo has partially been evidenced. Herein, we focus on the therapeutic merits of MSCs and also their derivative exosome as an innovative cell-free approach in AD, HD, PD, and ALS conditions. Also, we give a brief glimpse into novel approaches to potentiate MSC-induced therapeutic merits in such disorders, most importantly, administration of preconditioned MSCs.

• Differentiation
• Mesenchymal stromal cells (MSCs)
• Neuroinflammation
• Neuroprotection
• Neurotrophic factors (NTFs)

Transplantation of bone marrow mesenchymal stem cells has attracted more and more attention as a regenerative therapy for the treatment of liver diseases. A large number of studies have shown that this kind of cells can inhibit the activation of hepatic stellate cells and regulate tissue homeostasis and immune system via a variety of ways. Meanwhile, bone marrow mesenchymal stem cells can inhibit apoptosis of hepatocyte, improve liver function, and reduce inflammation through multiple pathways. These cells have a broad prospect in the treatment of liver cirrhosis. At present, there are many studies on the specific mechanism of bone marrow mesenchymal stem cells transplantation in the treatment of liver cirrhosis. This paper reviews the pathogenesis of liver cirrhosis and the mechanism of bone marrow mesenchymal stem cells transplantation in the treatment of liver cirrhosis, discusses the effectiveness of traditional Chinese medicine method in enhancing the efficacy of bone marrow mesenchymal stem cells transplantation, and looks forward to its application prospect in the future.

Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.

• Bone marrow
• Mesenchymal stem cells
• Liver fibrosis
• In vivo
• Efficiency

• Animals
• Bone Marrow
• Bone Marrow Cells
• Disease Models, Animal
• Humans
• Liver Cirrhosis/therapy
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells

End-stage liver fibrosis is common to all chronic liver diseases. Since liver transplantation has several limitations, including lack of donors, immunological rejection, and high medical costs, therapeutic alternatives are needed. The administration of mesenchymal stromal cells (MSCs) has been proven effective in tissue regeneration after damage. However, the risk of uncontrolled side effects, such as cellular rejection and tumorigenesis, should be taken into consideration. A safer alternative to MSC transplantation is represented by the MSC secretome, which retains the same beneficial effect of the cell of origin, without showing any considerable side effect. The paracrine effect of MSCs is mainly carried out by secreted particles in the nanometer range, known as extracellular vesicles (EVs) that play a fundamental role in intercellular communication. In this review, we discuss the current literature on MSCs and MSC-EVs, focusing on their potential therapeutic action in liver fibrosis and on their molecular content (proteins and RNA), which contributes in reverting fibrosis and prompting tissue regeneration.

• collagen
• exosomes
• fibrosis
• hepatic stellate cell
• inflammation
• mesenchymal stem cell
• microvesicles
• α-SMA

Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from that of umbilical cord mesenchymal stem cells (UCMSCs), such as higher expression levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and the FDA-approved drug pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury and acute respiratory distress syndrome, our findings suggest that IMRCs are ready for clinical trials on lung disorders.

Thyroid eye disease (TED) affects 25–50% of patients with Graves’ Disease. In TED, collagen accumulation leads to an expansion of the extracellular matrix (ECM) which causes destructive tissue remodeling. The purpose of this study was to investigate the therapeutic potential of activating the aryl hydrocarbon receptor (AHR) to limit ECM accumulation in vitro. The ability of AHR to control expression of matrix metalloproteinase-1 (MMP1) was analyzed. MMP1 degrades collagen to prevent excessive ECM. Human orbital fibroblasts (OFs) were treated with the pro-scarring cytokine, transforming growth factor beta (TGFβ) to induce collagen production. The AHR ligand, 6-formylindolo[3,2b]carbazole (FICZ) was used to activate the AHR pathway in OFs. MMP1 protein and mRNA levels were analyzed by immunosorbent assay, Western blotting and quantitative PCR. MMP1 activity was detected using collagen zymography. AHR and its transcriptional binding partner, ARNT were depleted using siRNA to determine their role in activating expression of MMP1. FICZ induced MMP1 mRNA, protein expression and activity. MMP1 expression led to a reduction in collagen 1A1 levels. Furthermore, FICZ-induced MMP1 expression required both AHR and ARNT, demonstrating that the AHR-ARNT transcriptional complex is necessary for expression of MMP1 in OFs. These data show that activation of the AHR by FICZ increases MMP1 expression while leading to a decrease in collagen levels. Taken together, these studies suggest that AHR activation could be a promising target to block excessive collagen accumulation and destructive tissue remodeling that occurs in fibrotic diseases such as TED.

• biomarkers
• liver diseases
• matrix metalloproteinases
• matrix remodeling
• therapeutics

• Animals
• Biomarkers/metabolism
• Disease Progression
• Humans
• Liver Diseases/enzymology
• Liver Diseases/etiology
• Liver Diseases/pathology
• Liver Diseases/therapy
• Matrix Metalloproteinases/chemistry
• Matrix Metalloproteinases/metabolism
• Molecular Targeted Therapy

The role of bone marrow-derived mesenchymal stem cells (BM-MSCs) in liver fibrosis remains poorly understood. This study aimed to use a mouse model of carbon tetrachloride (CCL₄)-induced liver fibrosis to investigate the effects of BM-MSCs during liver hypoxia and the involvement of the transforming growth factor beta 1 (TGF-β1) and SMADs pathway.

Thirty C57BL/6 mice were randomly divided into the control group (n=10), the model group (n=10), and the BM-MSC-treated model group (n=10). In the model group, liver fibrosis was induced by intraperitoneal injection of CCl₄. BM-MSCs were transplanted after 12 weeks of CCl₄ treatment. The serum biochemical parameters and histological changes in the liver, using histochemical stains, were investigated. The expression of collagen type I (collagen I), alpha-smooth muscle actin (α-SMA), TGF-β1, SMAD3, SMAD7, hypoxia-inducible factor 1 alpha (HIF-1α), and vascular endothelial grow factor (VEGF) were assessed by immunohistochemistry and quantitative real-time polymerase chain (RT-qPCR) reaction.

Treatment with BM-MSCs reduced the expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with the model group, and reduced liver fibrosis determined histologically using hematoxylin and eosin (H&E) and Masson’s trichrome staining compared with the model group. The area of liver fibrosis decreased after BM-MSCs treatment (p<0.05). Protein expression of HIF-1α and VEGF were decreased after BM-MSCs treatment (p<0.05). Transplantation of BM-MSCs reduced the mRNA expression of TGF-β1, collagen I, α-SMA, and SMAD3 (p<0.05).

BM-MSC transplantation reduced CCl₄-induced murine liver fibrosis, indicating that in a hypoxic microenvironment, BM-MSCs may inhibit the TGFβ-1/SMADs pathway.

• regeneration
• liver fibrosis

• Animals
• Bone Marrow Cells/cytology
• Bridged Bicyclo Compounds/pharmacology
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/therapy
• Collagen Type I/metabolism
• Enzyme Inhibitors/pharmacology
• Hexachlorophene/pharmacology
• Humans
• Immunohistochemistry
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/therapy
• Matrix Metalloproteinase 1/metabolism
• Matrix Metalloproteinase 14/metabolism
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Mice
• Mice, Inbred BALB C
• Temperature

• This work was supported by the project for realization of regenerative medicine, program for Creating STart-ups from Advanced Research and Technology from the Ministry of Education, Culture, Sports, Science and Technology in Japan, and KanonCure Inc..

End‐stage liver fibrosis frequently progresses to portal vein thrombosis, formation of oesophageal varices, hepatic encephalopathy, ascites, hepatocellular carcinoma and liver failure. Mesenchymal stem cells (MSCs), when transplanted in vivo, migrate into fibrogenic livers and then differentiate into hepatocyte‐like cells or fuse with hepatocytes to protect liver function. Moreover, they can produce various growth factors and cytokines with anti‐inflammatory effects to reverse the fibrotic state of the liver. In addition, only a small number of MSCs migrate to the injured tissue after cell transplantation; consequently, multiple studies have investigated effective strategies to improve the survival rate and activity of MSCs for the treatment of liver fibrosis. In this review, we intend to arrange and analyse the current evidence related to MSC transplantation in liver fibrosis, to summarize the detailed mechanisms of MSC transplantation for the reversal of liver fibrosis and to discuss new strategies for this treatment. Finally, and most importantly, we will identify the current problems with MSC‐based therapies to repair liver fibrosis that must be addressed in order to develop safer and more effective routes for MSC transplantation. In this way, it will soon be possible to significantly improve the therapeutic effects of MSC transplantation for liver regeneration, as well as enhance the quality of life and prolong the survival time of patients with liver fibrosis.

• improvement
• liver fibrosis
• mechanism
• mesenchymal stem cell
• regression

Autophagy is an evolutionarily conserved lysosome-dependent catabolic process which degrades cell components, including proteins and lipids, in order to recycle substrates to exert optimally and adapt to tough circumstances. It is an important mechanism for the body to maintain the homeostasis of the internal environment. Liver fibrosis refers to the excessive proliferation and abnormal deposition of extracellular matrix components in the liver tissue, resulting in pathological changes in liver structure and function abnormalities, which is seen in chronic liver diseases of many different causes. In this article, we summarizes the role of autophagy in hepatic fibrosis as well as the relevant signaling pathways to reveal the mechanism of autophagy in hepatic fibrosis.

• Autophagy
• Liver fibrosis
• Signaling pathway