• biological therapies
• inflammatory bowel disease
• intestinal immune microenvironment
• mesenchymal stem/stromal cells
• tissue regeneration

• Humans
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/metabolism
• Animals
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/therapy
• Inflammatory Bowel Diseases/pathology
• Mesenchymal Stem Cell Transplantation/methods
• Extracellular Vesicles/metabolism
• Extracellular Vesicles/immunology
• Regeneration/immunology
• Cellular Microenvironment/immunology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/pathology
• Immunomodulation

• ADSCs
• MNP
• endometrium
• hydrogel
• regeneration

• National Natural Science Foundation of China
• China Postdoctoral Science Foundation

• ADSC
• fibrosis
• histopathology
• kidney trauma
• stem cells
• total renal score

• Efficacy
• Liver cirrhosis
• Mesenchymal stem cells
• Meta-analysis
• Safety

• Humans
• Mesenchymal Stem Cell Transplantation/adverse effects
• Liver Cirrhosis/therapy
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/pathology

• QD088 First Affiliated Hospital of Gannan Medical University, Doctor Start-up Fund
• 32060232 the National Natural Science Foundation of China
• 20212BAB206075 The Jiangxi Provincial Natural Science Foundation

• Basic fibroblast growth factor
• Endoderm
• Epidermal growth factor
• Hepatic markers
• Hepatocyte growth factor
• Liver cirrhosis
• Liver transplantation
• Regenerative medicine

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the benefits and harms of stem cell treatment in adults with decompensated cirrhosis, regardless of ethnicity, sex, types of stem cells, route of stem cell injection, and administered dose.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation and their hepatogenic differentiated cells (HDCs) can be applied for liver injury repair by tissue grafting. Regenerative potentiality in liver cirrhosis models was widely investigated; however, immunomodulation and anti-inflammation in acute hepatitis remain unexplored. This study aimed to explore the immunomodulatory and evaluate twice intravenous (IV) or intrahepatic (IH) administration of either BM-MSCs or middle-stage HDCs on aflatoxin (AF) acute hepatitis rat model.

BM-MSCs viability, phenotypes, and proliferation were evaluated. Hepatogenic differentiation, albumin, and mmmmmmmm-fetoprotein gene expression were assessed. AF acute hepatitis was induced in rats using AFB1 supplementation. The transplantation of BM-MSCs or their HDCs was done either by IV or IH route. Hepatic ultrasound was performed after 3-weeks of therapy. Cytokines profile (tumor necrosis factor-α [TNF-α], interleukin [IL]-4, and IL-10) was assessed. Hepatic bio-indices, serum, and hepatic antioxidant activity were evaluated, besides examining liver histological sections.

Acute AFB1 showed a significant increase in TNF-α (p<0.01), liver enzyme activities (p<0.05), as well as decrease in IL-4, IL-10, and antioxidant enzyme activities (p<0.05). Cytokines profile was ameliorated in groups treated with IV and IH BM-MCs, showed a negative correlation between IL-4 and TNF-α (p<0.05), and a positive correlation between IL-10 upregulation and TNF-α (p<0.01). In IV HDCs treated group, positive correlations between IL-4 and IL-10 downregulation and TNF-α were observed. However, in IH HDCs group, a significant positive correlation between IL-4 and IL-10 upregulation and TNF-α, were recorded (p<0.05). In addition, IV BM-MSCs and IH HDCs treatments significantly increased antioxidant enzymes activity (p<0.05). IV and IH BM-MSCs significantly ameliorated liver transaminase levels, whereas IH HDCs significantly ameliorated alanine aminotransferase activity and nitric oxide concentration (p<0.05).

The administration routes of BM-MSCs did not demonstrate any significant difference; however, the IH route of HDCs showed significant amelioration from the IV route. On the other hand, it showed noticeable anti-inflammatory and immunomodulatory improvements in aflatoxicosis rats. Therefore, it can be concluded that acute hepatitis can be treated by a noninvasive IV route without the expense of hepatogenic differentiation. Further research using clinical trials that address several problems regarding engraftment and potentiation are needed to determine the optimal manipulation strategy as well as to achieve better long term effects.

• cell therapy
• drug-induced liver injury
• exosomes
• mesenchymal stem cells
• secretome

• Cyclophosphamide
• Green fluorescent protein
• Mesenchymal stem cell
• Premature ovarian failure

• Animals
• Cell Differentiation
• Cell Movement
• Cell Tracking/methods
• Cells, Cultured
• Cyclophosphamide
• Disease Models, Animal
• Female
• Green Fluorescent Proteins/genetics
• Green Fluorescent Proteins/metabolism
• Human Embryonic Stem Cells/cytology
• Human Embryonic Stem Cells/metabolism
• Humans
• Lung/cytology
• Lung/metabolism
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mice, Inbred C57BL
• Microscopy, Fluorescence/methods
• Myocardium/cytology
• Myocardium/metabolism
• Ovary/cytology
• Ovary/metabolism
• Primary Ovarian Insufficiency/chemically induced
• Primary Ovarian Insufficiency/metabolism
• Primary Ovarian Insufficiency/therapy
• Mice

The therapeutic value of mesenchymal stem cells (MSCs) for the treatment of infectious diseases and the repair of disease-induced tissue damage has been explored extensively. MSCs inhibit inflammation, reduce pathogen load and tissue damage encountered during infectious diseases through the secretion of antimicrobial factors for pathogen clearance and they phagocytose certain bacteria themselves. MSCs dampen tissue damage during infection by downregulating the levels of pro-inflammatory cytokines, and inhibiting the excessive recruitment of neutrophils and proliferation of T cells at the site of injury. MSCs aid in the regeneration of damaged tissue by differentiating into the damaged cell types or by releasing paracrine factors that direct tissue regeneration, differentiation, and wound healing. In this review, we discuss in detail the various mechanisms by which MSCs help combat pathogens, tissue damage associated with infectious diseases, and challenges in utilizing MSCs for therapy.

• Infectious diseases
• Mesenchymal stem cells
• Antimicrobial effect
• Immunomodulation
• Tissue repair
• COVID-19

The liver is an organ with impressive regenerative potential and has been shown to heal sizable portions after their removal. However, certain diseases can overstimulate its potential to self-heal and cause excessive cellular matrix and collagen buildup. Decompensation of liver fibrosis leads to cirrhosis, a buildup of fibrotic ECM that impedes the liver’s ability to efficiently exchange fluid. This review summarizes the complex immunological activities in different liver diseases, and how failure to maintain liver homeostasis leads to progressive fibrotic tissue development. We also discuss a variety of pathologies that lead to liver cirrhosis, such as alcoholic liver disease and chronic hepatitis B virus (HBV). Mesenchymal stem cells are widely studied for their potential in tissue replacement and engineering. Herein, we discuss the potential of MSCs to regulate immune response and alter the disease state. Substantial efforts have been performed in preclinical animal testing, showing promising results following inhibition of host immunity. Finally, we outline the current state of clinical trials with mesenchymal stem cells and other cellular and non-cellular therapies as they relate to the detection and treatment of liver cirrhosis.

• alcoholic liver disease
• apoptosis
• autoimmune disease
• cirrhosis
• clinical trials
• cytokines
• fibrosis
• hepatitis
• hepatocyte
• immunomodulation
• in vivo
• liver
• mesenchymal stem cells
• non-alcoholic fatty liver disease

• Animals
• Biomarkers
• Combined Modality Therapy
• Disease Management
• Disease Progression
• Disease Susceptibility/immunology
• Host-Pathogen Interactions/genetics
• Host-Pathogen Interactions/immunology
• Humans
• Liver Diseases/diagnosis
• Liver Diseases/etiology
• Liver Diseases/metabolism
• Liver Diseases/therapy
• Translational Research, Biomedical

• R25 GM109441 NIGMS NIH HHS
• T32 GM007057 NIGMS NIH HHS

Mesenchymal stem cell (MSC) transplantation is a novel treatment for liver diseases due to the roles of MSCs in regeneration, fibrosis inhibition and immune regulation. However, the mechanisms are still not completely understood. Despite the significant efficacy of MSC therapy in animal models and preliminary clinical trials, issues remain. The efficacy and safety of MSC-based therapy in the treatment of liver diseases remains a challenging issue that requires more investigation. This article reviews recent studies on the mechanisms of MSCs in liver diseases and the associated challenges and suggests potential future applications.

• efficacy
• liver diseases
• mechanism
• mesenchymal stem cells
• safety

Bone marrow mesenchymal stromal cells (BM-MSCs) are multipotent stem cells which are ideal candidates for use in regenerative medicine. The objectives of this study were to evaluate the hepatoprotective effect of BM-MSC and its combination treatment with silymarin in carbon tetrachloride (CCl₄)-induced liver cirrhosis animal model and to investigate whether tail vein or portal vein infusion was the ideal route for BM-MSC transplantation. 36 female Wistar rats were randomly divided into six groups (n = 6): Group 1 (normal control), Group 2 (received only CCl₄, disease model), Group 3 (CCl₄ + BM-MSCs through tail vein), Group 4 (CCl₄ + BM-MSCs through portal vein), Group 5 (CCl₄ + silymarin), Group 6 (CCl₄ + BM-MSCs + silymarin). On the 21st day after treatment, blood samples were collected for biochemical estimations. After the experiment, the rats were sacrificed. Liver was dissected out and processed for histopathology and scanning electron microscopy studies. Liver enzyme and marker analysis, histopathological studies indicated that the combination of BM-MSCs and silymarin was effective in treating liver cirrhosis. Transplanted BM-MSCs in combination with silymarin ameliorated the liver tissue damage through their immunoregulatory activities. Among the two routes, the intravenous administration of cells through the tail vein was found to be more effective and safe.

• Liver cirrhosis
• Mesenchymal stromal cells
• Multipotent
• Regeneration

• Manipal Academy of Higher Education, Manipal

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

• biomaterials
• ectoderm
• embryonic stem cells
• endoderm
• induced pluripotent stem cells
• mesenchymal stem cells
• mesoderm
• regenerative medicine
• stem cells

• Hematopoietic
• Mesenchymal
• Progenitor

Liver fibrosis is a major medical problem with high mortality and morbidity rates where the formation of regenerative nodules and cirrhosis leads to loss of liver function and may result in the development of hepatocellular carcinoma. bone marrow mesenchymal stem cells (BM-MSCs) have drawn attention as a novel approach for treatment of liver fibrosis. This study aimed to evaluate the therapeutic effect of BM-MSCs on the liver structure in carbon tetrachloride (CCl₄) induced liver fibrosis in male rats relative to resveratrol and Silybum marianum as standard drugs derived from herbal plants.

Fifty adult male albino rats (Sprague Dawley strain; 180–220 g mean body weight) were purchased from the Laboratory Animal Unit in the Nile Center of Experimental Research, Mansoura, Egypt. Liver function were determined, isolation and preparation of BM- MSCs and detection of cell-surface markers by flow cytometry.

Animals exposed to CCl₄ developed liver injury characterized by significant increase of liver enzymes, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), and CYP450, inhibition of antioxidant enzymes, and decreased albumin. Treatment with stem cells enhanced liver state more effectively than resveratrol and S. marianum. It significantly decreased AST, ALT, ALP, MDA, TNF-α, and CYP450 and increased albumin, SOD, GSH, GST, and CAT. Histopathological study and atomic force microscope results confirmed the therapeutic effects of MSCs.

BM-MSCs could restore liver structure and function in CCL₄ induced liver fibrosis rat model, ameliorating the toxicity of CCl₄ and improving liver function tests.

• Bone marrow mesenchymal stem cells
• CYP450
• liver fibrosis

• LLLI
• Nrf2
• Radiation protection

• Animals
• Antioxidants/metabolism
• Cell Differentiation/radiation effects
• Cell Line
• Cell Proliferation/radiation effects
• Gene Expression Regulation/radiation effects
• Humans
• Lasers/adverse effects
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/radiation effects
• Mice
• NF-E2-Related Factor 2/genetics
• Radiation Protection
• Umbilical Cord/radiation effects

• Anti-fibrotic mechanisms of action
• Clinical trials
• Fibrosis
• Heterogeneity
• Mesenchymal stromal cells
• Pre-clinical animal models

• cell hypoxia
• liver cirrhosis, experimental
• mesenchymal stromal cells

• Alanine Transaminase/metabolism
• Animals
• Aspartate Aminotransferases/metabolism
• Bone Marrow/metabolism
• Carbon Tetrachloride/pharmacology
• Cell Hypoxia/physiology
• China
• Disease Models, Animal
• Fibrosis/metabolism
• Fibrosis/physiopathology
• Hypoxia/pathology
• Hypoxia-Inducible Factor 1, alpha Subunit
• Liver/pathology
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/pathology
• Liver Cirrhosis/therapy
• Male
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/physiology
• Mice
• Mice, Inbred C57BL
• Smad Proteins/metabolism
• Smad Proteins/physiology
• Transforming Growth Factor beta/metabolism

Osteoporosis is a systemic bone metabolic disease, which often occurs among the elderly. Angelica polysaccharide (AP) is the main component of angelica sinensis, and is widely used for treating various diseases. However, the effects of AP on osteoporosis have not been investigated. This study aimed to uncover the functions of AP in mesenchymal stem cell (MSC) proliferation and osteoblast differentiation.

MSCs were treated with different concentrations of AP, and then cell viability, Cyclin D1 protein level, and the osteogenic markers of runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP-2) were examined by Cell Counting Kit-8 (CCK-8) and western blot assays, respectively. The effect of AP on the main signalling pathways of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin was determined by western blot. Following this, si-H19#1 and si-H19#2 were transfected into MSCs, and the effects of H19 on cell proliferation and osteoblast differentiation in MSCs were studied. Finally, in vivo experimentation explored bone mineral density, bone mineral content, and the ash weight and dry weight of femoral bone.

The results revealed that AP significantly promoted cell viability, upregulated cyclin D1 and increased RUNX2, OCN, ALP, and BMP-2 protein levels in MSCs. Moreover, we found that AP notably activated PI3K/AKT and Wnt/β-catenin signalling pathways in MSCs. Additionally, the relative expression level of H19 was upregulated by AP in a dose-dependent manner. The promoting effects of AP on cell proliferation and osteoblast differentiation were reversed by H19 knockdown. Moreover, in vivo experimentation further confirmed the promoting effect of AP on bone formation.

These data indicate that AP could promote MSC proliferation and osteoblast differentiation by regulating H19.

Cite this article: X. Xie, M. Liu, Q. Meng. Angelica polysaccharide promotes proliferation and osteoblast differentiation of mesenchymal stem cells by regulation of long non-coding RNA H19: An animal study. Bone Joint Res 2019;8:323–332. DOI: 10.1302/2046-3758.87.BJR-2018-0223.R2.

• Angelica polysaccharide
• Long non-coding RNA H19
• Osteoporosis
• Phosphatidylinositol 3-kinase/protein kinase B
• Wnt/β-catenin

Researchers have used dogs with neurological sequelae caused by distemper as an experimental model for multiple sclerosis, owing to the similarities of the neuropathological changes between distemper virus-induced demyelinating leukoencephalitis and multiple sclerosis in humans. However, little is known about the role of mesenchymal stem cells in treating such clinical conditions. Therefore, we investigated the use of mesenchymal stem cells in four dogs with neurological lesions caused by the distemper virus. During the first year after cellular therapy, the animals did not demonstrate significant changes in their locomotive abilities. However, the intense (Grade V) myoclonus in three animals was reduced to a moderate (Grade IV) level. At one year after the mesenchymal stem cell infusions, three animals regained functional ambulation (Grade I), and all four dogs started to move independently (Grades I and II). In two animals, the myoclonic severity had become mild (Grade III). It was concluded that the use of mesenchymal stem cells could improve the quality of life of dogs with neurological sequelae caused by canine distemper, thus presenting hope for similar positive results in human patients with multiple sclerosis.

• Canine distemper
• Cell biology
• Demyelination
• Mesenchymal stem cells
• Multiple sclerosis
• Neuroscience

• CD34-ve cells
• Mesenchymal stem cells
• cell therapy
• hepatic regeneration
• immune response
• liver fibrosis

• Hepatocyte proliferation
• Liver regeneration
• Mesenchymal stem cells
• Partial hepatectomy
• Stem cells

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

• Dermofasciectomy
• Dupuytren disease
• Fasciectomy
• Fat grafting
• Lipofilling
• Minimally invasive
• Needle aponeurotomy
• Needle fasciotomy

• endophthalmitis
• inflammation
• ocular microbial infections
• stem cells
• tissue regeneration

• Animals
• Anti-Infective Agents/adverse effects
• Anti-Infective Agents/therapeutic use
• Eye Infections/drug therapy
• Eye Infections/therapy
• Humans
• Mesenchymal Stem Cell Transplantation/methods
• Mice

• Adenine/toxicity
• Adipose Tissue/cytology
• Animals
• Cells, Cultured
• Fibrosis/genetics
• Gene Expression Profiling
• Humans
• Kidney Diseases/chemically induced
• Kidney Diseases/genetics
• Kidney Diseases/prevention & control
• Male
• Rats
• Rats, Wistar
• Stem Cells/cytology

Cisplatin is a powerful antitumor chemotherapeutic agent that is widely used in the treatment of many cancers but it has many side effects on many organs including salivary glands. Bone marrow is considered to be a rich environment that comprises many types of stem cells of which BMSCs (Bone marrow mesenchymal stem cells) are the most studied with potentiality to differentiate into many cell types. This study was conducted to evaluate the effect of different routes of injection of BMSCs on parotid glands of rats receiving cisplatin.

Sprague-Dawley rats were divided into 3 groups: a negative control group receiving phosphate buffered saline, a positive control group receiving cisplatin, and an experimental group where rats received cisplatin and then received iron oxide-labeled BMSCs by either intravenous or intraparotid routes or both. Animals were sacrificed at periods of 3,6,10 and 15 days after cisplatin injection, then histological, ultrastructural and immunohistochemical studies were done. The experimental stem cell treated group showed better histological features and increased PCNA proliferation index when compared to the control. The systemic and combination groups showed better results than the local group. Iron oxide-labeled cells were detected with Prussian blue stain.

This study proved that BMSCs can improve cisplatin induced cytotoxicity in parotid glands. Systemic administration showed to have a better effect than local intraparotid administration and comparable effect to combined administration.

• Bone marrow
• Chemotherapy
• Immunohistochemistry
• Parotid gland
• Stem cells
• Transmission electron microscopy

• Adipose-derived mesenchymal stem cell
• Amino acid
• Canine
• Superficial necrolytic dermatitis

• adipose-derived mesenchymal stem cells
• bone marrow mesenchymal stem cells
• hepatotoxicity
• methotrexate
• nephrotoxicity

• Acute Kidney Injury/chemically induced
• Acute Kidney Injury/metabolism
• Acute Kidney Injury/pathology
• Acute Kidney Injury/therapy
• Allografts
• Animals
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/pathology
• Chemical and Drug Induced Liver Injury/therapy
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/metabolism
• Methotrexate/adverse effects
• Methotrexate/pharmacology
• Rats
• Rats, Wistar

Mesenchymal stromal cells (MSCs) from various tissues have shown moderate therapeutic efficacy in reversing liver fibrosis in preclinical models. Here, we compared the relative therapeutic potential of pooled, adult human bone marrow (BM)- and neonatal Wharton’s jelly (WJ)-derived MSCs to treat CCl₄-induced liver fibrosis in rats.

Sprague-Dawley rats were injected with CCl₄ for 8 weeks to induce irreversible liver fibrosis. Ex-vivo expanded, pooled human MSCs obtained from BM and WJ were intravenously administered into rats with liver fibrosis at a dose of 10 × 10⁶ cells/animal. Sham control and vehicle-treated animals served as negative and disease controls, respectively. The animals were sacrificed at 30 and 70 days after cell transplantation and hepatic-hydroxyproline content, histopathological, and immunohistochemical analyses were performed.

BM-MSCs treatment showed a marked reduction in liver fibrosis as determined by Masson’s trichrome and Sirius red staining as compared to those treated with the vehicle. Furthermore, hepatic-hydroxyproline content and percentage collagen proportionate area were found to be significantly lower in the BM-MSCs-treated group. In contrast, WJ-MSCs treatment showed less reduction of fibrosis at both time points. Immunohistochemical analysis of BM-MSCs-treated liver samples showed a reduction in α-SMA⁺ myofibroblasts and increased number of EpCAM⁺ hepatic progenitor cells, along with Ki-67⁺ and human matrix metalloprotease-1⁺ (MMP-1⁺) cells as compared to WJ-MSCs-treated rat livers.

Our findings suggest that BM-MSCs are more effective than WJ-MSCs in treating liver fibrosis in a CCl₄-induced model in rats. The superior therapeutic activity of BM-MSCs may be attributed to their expression of certain MMPs and angiogenic factors.

• Angiogenesis
• Human BM- and WJ-MSCs
• Liver fibrosis
• MMPs

• Anti-inflammatory
• Antifibrotic
• Human umbilical cord mononuclear cells
• Liver fibrosis
• Mouse bone marrow cells
• Sylimarin

• Alanine Transaminase/metabolism
• Animals
• Aspartate Aminotransferases/metabolism
• Bone Marrow Cells/cytology
• Bone Marrow Cells/metabolism
• Carbon Tetrachloride/pharmacology
• Cells, Cultured
• Collagen/metabolism
• Glutathione/metabolism
• Hepatocytes/cytology
• Hepatocytes/metabolism
• Humans
• Laminin/metabolism
• Leukocytes, Mononuclear/cytology
• Leukocytes, Mononuclear/metabolism
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/therapy
• Male
• Malondialdehyde/metabolism
• Mice
• Oxidative Stress/physiology
• Transforming Growth Factor beta1/metabolism
• Tumor Necrosis Factor-alpha/metabolism
• Umbilical Cord/cytology
• Umbilical Cord/metabolism

• IPCs
• MSCs
• STZ
• Therapeutic trial
• Type 1diabetes

Hepatocyte-like cells (HLCs) are generated from either various human pluripotent stem cells (hPSCs) including induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), or direct cell conversion, mesenchymal stem cells as well as other stem cells like gestational tissues. They provide potential cell sources for biomedical applications. Liver transplantation is the gold standard treatment for the patients with end stage liver disease, but there are many obstacles limiting this process, like insufficient number of donated healthy livers. Meanwhile, the number of patients receiving a liver organ transplant for a better life is increasing. In this regard, HLCs may provide an adequate cell source to overcome these shortages. New molecular engineering approaches such as CRISPR/ Cas system applying in iPSCs technology provide the basic principles of gene correction for monogenic inherited metabolic liver diseases, as another application of HLCs. It has been shown that HLCs could replace primary human hepatocytes in drug discovery and hepatotoxicity tests. However, generation of fully functional HLCs is still a big challenge; several research groups have been trying to improve current differentiation protocols to achieve better HLCs according to morphology and function of cells. Large-scale generation of functional HLCs in bioreactors could make a new opportunity in producing enough hepatocytes for treating end-stage liver patients as well as other biomedical applications such as drug studies. In this review, regarding the biomedical value of HLCs, we focus on the current and efficient approaches for generating hepatocyte-like cells in vitro and discuss about their applications in regenerative medicine and drug discovery.

• Cell Therapy
• Drug Discovery
• Gene Therapy
• Hepatocyte

• Acute necrotizing pancreatitis
• Aquaporin 1
• Capillary leakage
• Intestinal injury
• Mesenchymal stem cells

• basal ganglia
• hepatic encephalopathy
• hippocampus
• liver
• stem cells

• CCl4 liver fibrosis
• bone marrow stem cell
• stem cell therapy
• umbilical cord blood CD34+