Cell Therapy For Liver Diseases Research Articles

Stem Cell Therapy for Liver Diseases: Current Perspectives.

Stem cell therapy offers a promising avenue for advanced liver disease cases as an alternative to liver transplantation. Clinical studies are underway to explore the potential of stem cells from various sources in treating different liver diseases. However, due to the variability among current studies, further validation is needed to ensure the safety and effectiveness of stem cell therapy. To establish a strong foundation for optimal stem cell therapy applications, selection of suitable stem cell sources, standardization of transplantation protocols, and patient criteria are vital. This review comprehensively examines existing literature on stem cell sources, transplantation methods, and patient selection. Additionally, we discuss novel strategies, including stem cell preconditioning, cell-free therapy, genetic modification of stem cells, and the use of liver organoids, addressing the limitations of current stem cell therapies. Nevertheless, these innovative approaches require further validation.

Hypoimmunogenic Human Pluripotent Stem Cells as a Powerful Tool for Liver Regenerative Medicine.

Induced pluripotent stem cells (iPSC) have huge potential as cell therapy for various diseases, given their potential for unlimited self-renewal and capability to differentiate into a wide range of cell types. Although autologous iPSCs represents the ideal source for patient-tailored regenerative medicine, the high costs of the extensive and time-consuming production process and the impracticability for treating acute conditions hinder their use for broad applications. An allogeneic iPSC-based strategy may overcome these issues, but it carries the risk of triggering an immune response. So far, several approaches based on genome-editing techniques to silence human leukocyte antigen class I (HLA-I) or II (HLA-II) expression have been explored to overcome the immune rejection of allogeneic iPSCs. In this study, we employed the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9) system to delete the β2-Microglobulin (B2M) and the Class II Major Histocompatibility Complex Transactivator (CIITA) genes, essential for the correct surface expression of HLA-I and HLA-II proteins. The resulting hypoimmunogenic iPSC line has a normal karyotype, expresses the pluripotency stem cell markers, and is capable of differentiating into the three embryonic germ layers. Furthermore, we showed that it specifically retains the ability to differentiate towards different liver cells, such as endothelial-like cells, hepatocyte-like cells, and hepatic stellate-like cells. Our results indicate that hypoimmunogenic iPSCs could give a new cost-effective and off-the-shelf opportunity for cell therapy in liver diseases.

Recent advances in the immunomodulation mechanism of mesenchymal stem cell therapy in liver diseases.

Liver fibrosis, acute liver injury or liver failure, liver tumors, and immune rejection after liver transplantation are common clinical liver diseases. Immune responses are the key to determining the prognosis of liver diseases. Liver transplantation could be the last resort for patients with liver failure. However, the use of liver transplantation is limited because of the scarcity of organ donors, immunological rejection in recipients, and high cost. Mesenchymal stem cells (MSCs) are pluripotent adult stem cells with extensive anti-inflammatory and immunomodulation effects. MSCs can be effectively used for treating liver diseases but without the limitations that are associated with liver transplantation. Therefore, several clinical trials have utilized MSCs for the treatment of refractory liver diseases and the related mechanism is increasingly being elucidated. We have mainly summarized the recent studies that focus on the immunomodulation mechanism of MSC therapy in liver diseases. Further, we have presented our insights on the prospects of using MSCs in the treatment of liver diseases.

Protective effect of adipose-derived stromal cell-secretome attenuate autophagy induced by liver ischemia–reperfusion and partial hepatectomy

BackgroundThe therapeutic effects of adipose-derived mesenchymal stromal cells (ADSCs) may be mainly mediated by their paracrine effects. The ADSC-secretome can ameliorate hepatic ischemia–reperfusion injury (IRI). We explored the therapeutic effect of the ADSC-secretome from the perspective of excessive hepatocyte autophagy induced by hepatic IRI.MethodsWe established a miniature pig model of hepatic ischemia–reperfusion (I/R) and hepatectomy using a laparoscopic technique and transplanted ADSCs and the ADSC-secretome into the liver parenchyma immediately after surgery. Liver injury and hepatocyte autophagy were evaluated by histopathological examination and assessment of relevant cytokines and other factors.ResultsThe results showed that the ADSC-secretome alleviated the pathological changes of liver tissue and the microstructural damage of hepatocytes after IRI. Moreover, the expression levels of autophagy-related markers including Beclin-1, ATG5, ATG12, and LC3II/LC3I decreased, whereas those of p62 increased during phagophore expansion. Furthermore, the expression levels of markers related to the autophagy inhibition pathway phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR), including PI3K, Akt, and mTOR, increased.ConclusionThe ADSC-secretome attenuates hepatic I/R and hepatectomy-induced liver damage by inhibiting autophagy, which is possibly mediated by activation of the PI3K/Akt/mTOR signaling pathway. In addition, there was no significant difference between ADSCs and the ADSC-secretome in the regulation of hepatocyte autophagy. Therefore, ADSCs may improve the excessive autophagy-induced injury of hepatocytes in hepatic I/R and hepatectomy through paracrine effect. Our findings provide new insight into the therapeutic potential of cell-free products, which could replace cell therapy in liver diseases.

Liver Regeneration by Hematopoietic Stem Cells: Have We Reached the End of the Road?

The liver is the organ with the highest regenerative capacity in the human body. However, various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Despite advances in surgery and pharmacological treatments, liver diseases remain a leading cause of death worldwide. To address the shortage of donor liver organs for orthotopic liver transplantation, cell therapy in liver disease has emerged as a promising regenerative treatment. Sources include primary hepatocytes or functional hepatocytes generated from the reprogramming of induced pluripotent stem cells (iPSC). Different types of stem cells have also been employed for transplantation to trigger regeneration, including hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs) as well as adult and fetal liver progenitor cells. HSCs, usually defined by the expression of CD34 and CD133, and MSCs, defined by the expression of CD105, CD73, and CD90, are attractive sources due to their autologous nature, ease of isolation and cryopreservation. The present review focuses on the use of bone marrow HSCs for liver regeneration, presenting evidence for an ongoing crosstalk between the hematopoietic and the hepatic system. This relationship commences during embryogenesis when the fetal liver emerges as the crossroads between the two systems converging the presence of different origins of cells (mesoderm and endoderm) in the same organ. Ample evidence indicates that the fetal liver supports the maturation and expansion of HSCs during development but also later on in life. Moreover, the fact that the adult liver remains one of the few sites for extramedullary hematopoiesis—albeit pathological—suggests that this relationship between the two systems is ongoing. Can, however, the hematopoietic system offer similar support to the liver? The majority of clinical studies using hematopoietic cell transplantation in patients with liver disease report favourable observations. The underlying mechanism—whether paracrine, fusion or transdifferentiation or a combination of the three—remains to be confirmed.

SAT212 - 3D bioprinted hepatocyte and mesenchymal stem cell spheroids as a cell therapy for liver disease

SAT212 - 3D bioprinted hepatocyte and mesenchymal stem cell spheroids as a cell therapy for liver disease

Current status, challenges and reflections on stem cell therapy for liver diseases

There are increasing number of clinical studies on the use of stem cells in the treatment of liver diseases. Most studies have shown that stem cells can significantly improve liver function and prolong survival in patients with decompensated cirrhosis and liver failure. However, the current study has high heterogeneity and few mechanistic research data, which cannot answer many key questions about stem cell therapy for liver diseases. This paper reviews the research status of stem cells, in order to clarify the existing problems and challenges, and puts forward some reflections and countermeasures, with hope to promote the clinical application of stem cells in the treatment of liver diseases.

Clinical research in cell therapy of liver diseases: progress and challenges

The high incidence of chronic liver disease is a serious threat to public health, and the current comprehensive internal medicine treatment is ineffective. Liver transplantation is limited by the shortage of liver source and post-transplant rejection, and thus unmet the clinical needs. More importantly, cell therapy shows great promise for the treatment of chronic liver disease. Over recent years, domestic and foreign scholars have carried out a variety of cell therapy preclinical and clinical trials for critical liver disease, and achieved certain results, providing new methods for the treatment of chronic liver diseases. This review discusses the cell therapy research status and application progress, various existing problems and challenges, and key issues of mesenchymal stem cells in the treatment of chronic liver diseases.

Single cell Raman spectroscopy to identify different stages of proliferating human hepatocytes for cell therapy

BackgroundCell therapy provides hope for treatment of advanced liver failure. Proliferating human hepatocytes (ProliHHs) were derived from primary human hepatocytes (PHH) and as potential alternative for cell therapy in liver diseases. Due to the continuous decline of mature hepatic genes and increase of progenitor like genes during ProliHHs expanding, it is challenge to monitor the critical changes of the whole process. Raman microspectroscopy is a noninvasive, label free analytical technique with high sensitivity capacity. In this study, we evaluated the potential and feasibility to identify ProliHHs from PHH with Raman spectroscopy.MethodsRaman spectra were collected at least 600 single spectrum for PHH and ProliHHs at different stages (Passage 1 to Passage 4). Linear discriminant analysis and a two-layer machine learning model were used to analyze the Raman spectroscopy data. Significant differences in Raman bands were validated by the associated conventional kits.ResultsLinear discriminant analysis successfully classified ProliHHs at different stages and PHH. A two-layer machine learning model was established and the overall accuracy was at 84.6%. Significant differences in Raman bands have been found within different ProliHHs cell groups, especially changes at 1003 cm−1, 1206 cm−1 and 1440 cm−1. These changes were linked with reactive oxygen species, hydroxyproline and triglyceride levels in ProliHHs, and the hypothesis were consistent with the corresponding assay results.ConclusionsIn brief, Raman spectroscopy was successfully employed to identify different stages of ProliHHs during dedifferentiation process. The approach can simultaneously trace multiple changes of cellular components from somatic cells to progenitor cells.

Functional hit 1 (FH1)-based rapid and efficient generation of functional hepatocytes from human mesenchymal stem cells: a novel strategy for hepatic differentiation.

BackgroundBecause the liver is central to the physiology of the body, primary hepatocytes are widely used in liver pathology and physiological research, such as liver drug screening, bioartificial liver support system, and cell therapy for liver diseases. However, the source of primary hepatocytes is limited. We describe a novel non-transgenic protocol that facilitates the rapid generation of hepatocyte-like cells from human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), providing a new source of functional hepatocytes.MethodsIn this study, we used hUC-MSCs and human induced pluripotent cells (iPSCs) derived mesenchymal stem cells (iMSCs) to investigate the new induction strategy. Passage 3 MSCs were induced into hepatocyte-like cells using small-molecule compounds combined with cell factors in vitro. Functional hit 1 (FH1), a promising small molecule compound was achieved to replace HGF in the hepatocyte maturation stage to induce the hepatocyte-like cells differentiation.ResultsWe rapidly induced hUC-MSCs and human iMSCs into hepatocyte-like cells within 10 days in vitro, and the cells were morphologically similarly to both hepatocytes derived from the hepatocyte growth factor (HGF)-based method and the primary hepatocytes. They expressed mature hepatocyte special genes and achieved functions such as glycogen storage, albumin expression, urea secretion, cytochrome P450 activity, Low-density lipoprotein (LDL) uptake, and indocyanine green (ICG) uptake.ConclusionsWe successfully established a small-molecule protocol without using HGF to differentiate MSCs into hepatocyte-like cells, which provides a rapid and cost-effective platform for in vitro studies of liver disease.

Comparative analysis of delivery methods for stem cell therapy in liver diseases

Background: Mesenchymal stem cell transplantation is an emerging therapy for treating acute and chronic liver diseases as an alternative for patients who are not transplant candidates. The potential of this treatment depends on its therapeutic efficiency and safety, which have been investigated and evaluated in both preclinical and clinical settings. However, there are still some risks associated with the delivery methods, such as low long-term retention rate and the possibility of arousing cancer or rejection. Methods: During the review process, previous papers mentioning “stem cell treatment” and “liver diseases” were searched. We described different up-to-date approaches for stem cells from various origins to be delivered to the liver and compared respectively their pros and cons for clinical applications. We also proposed several potential techniques for future studies. Summary: An efficient and safe stem cell delivery could be enabled via Alginate-Polylysine-Alginate (APA) microencapsulation, lipid-conjugated coating or the use of nanoparticles. Their efficacy will be improved through tissue engineering and microrobots as the delivery is sustained and targeted with fewer rejection responses.

Assessment of long-term functional maintenance of primary human hepatocytes to predict drug-induced hepatoxicity in vitro.

Hepatocytes are the main cell components of the liver and perform metabolic,detoxification, and endocrine functions. Functional hepatocytes are of great value in drug development, toxicity evaluation, and cell therapy for liver diseases. In recent years, an increasing number of in vitro models have been developed to screen drugs and test their toxicity. However, maintaining hepatocyte function in vitro for a long time is a serious challenge. Even freshly isolated liver cells cultured for a short time may lose function via spontaneous dedifferentiation. Thus, novel cell culture systems allowing extended hepatocyte maintenance and more predictive long-term in vitro studies are required. In this study, we developed a conditioned culture system composed of a small-molecule combination that can maintain hepatocyte morphology and functions over the long term. Two-month culture of primary human hepatocytes showed that the conditioned medium was able to stably preserve hepatic functions such as albumin and α-antitrypsin secretion, hepatic transport activity, urea synthesis, and ammonia elimination. Furthermore, this culture model can be used to assess drug-induced hepatotoxicity in vitro. In summary, our work suggests a feasible approach to maintain hepatocyte function in vitro and proposes a promising model for long-term toxicological studies and drug development.

Mesenchymal stem cell therapy for liver disease: current status and future perspectives.

Liver transplantation is the gold standard for the treatment of end-stage liver disease. However, a shortage of donor organs, high cost, and surgical complications limit the use of this treatment. Cellular therapies using hepatocytes, hematopoietic stem cells, bone marrow mononuclear cells, and mesenchymal stem cells (MSCs) are being investigated as alternative treatments to liver transplantation. The purpose of this review is to describe studies using MSC transplantation for liver diseases based on the reported literature and to discuss prospective research designed to improve the efficacy of MSC therapy. MSCs have several properties that show potential to regenerate injured tissues or organs, such as homing, transdifferentiation, immunosuppression, and cellular protective capacity. Additionally, MSCs can be noninvasively isolated from various tissues and expanded ex vivo in sufficient numbers for clinical evaluation. Currently, there is no approved MSC therapy for the treatment of liver disease. However, MSC therapy is considered a promising alternative treatment for end-stage liver diseases and is reported to improve liver function safely with no side effects. Further robust preclinical and clinical studies will be needed to improve the therapeutic efficacy of MSC transplantation.

Cell Therapy for Liver Disease: From Promise to Reality.

Over the last decade, there has been a considerable progress in the development of cell therapy products for the treatment of liver diseases. The quest to generate well-defined homogenous cell populations with defined mechanism(s) of action has enabled the progression from use of autologous bone marrow stem cells comprising of heterogeneous cell populations to allogeneic cell types such as monocyte-derived macrophages, regulatory T cells, mesenchymal stromal cells, macrophages, etc. There is growing evidence regarding the multiple molecular mechanisms pivotal to various therapeutic effects and hence, careful selection of cell therapy product for the desired putative effects is crucial. In this review, we have presented an overview of the cell therapies that have been developed thus far, with preclinical and clinical evidence for their use in liver disease. Limitations associated with these therapies have also been discussed. Despite the advances made, there remain multiple challenges to overcome before cell therapies can be considered as viable treatment options, and these include larger scale clinical trials, scalable production of cells according to good manufacturing practice standards, pathways for delivery of cell therapy within hospital environments, and costs associated with the production.

Maintenance of Primary Hepatocyte Functions In Vitro by Inhibiting Mechanical Tension-Induced YAP Activation

Hepatocytes are the primary functional cells of the liver, performing its metabolic, detoxification, and endocrine functions. Functional hepatocytes are extremely valuable in drug discovery and evaluation, as well as in cell therapy for liver diseases. However, it has been a long-standing challenge to maintain the functions of hepatocytes invitro. Even freshly isolated hepatocytes lose essential functions after short-term culture for reasons that are still not well understood. In the present study, we find that mechanical tension-induced yes-associated protein activation triggers hepatocyte dedifferentiation. Alleviation of mechanical tension by confining cell spreading is sufficient to inhibit hepatocyte dedifferentiation. Based on this finding, we identify a small molecular cocktail through reiterative chemical screening that can maintain hepatocyte functions over the long term and invivo repopulation capacity by targeting actin polymerization and actomyosin contraction. Our work reveals the mechanisms underlying hepatocyte dedifferentiation and establishes feasible approaches to maintain hepatocyte functions.

Mesenchymal Stem Cells in the Adult Human Liver: Hype or Hope?

Chronic liver diseases constitute a significant economic, social, and biomedical burden. Among commonly adopted approaches, only organ transplantation can radically help patients with end-stage liver pathologies. Cell therapy with hepatocytes as a treatment for chronic liver disease has demonstrated promising results. However, quality human hepatocytes are in short supply. Stem/progenitor cells capable of differentiating into functionally active hepatocytes provide an attractive alternative approach to cell therapy for liver diseases, as well as to liver-tissue engineering, drug screening, and basic research. The application of methods generally used to isolate mesenchymal stem cells (MSCs) and maintain them in culture to human liver tissue provides cells, designated here as liver MSCs. They have much in common with MSCs from other tissues, but differ in two aspects—expression of a range of hepatocyte-specific genes and, possibly, inherent commitment to hepatogenic differentiation. The aim of this review is to analyze data regarding liver MSCs, probably another type of liver stem/progenitor cells different from hepatic stellate cells or so-called hepatic progenitor cells. The review presents an analysis of the phenotypic characteristics of liver MSCs, their differentiation and therapeutic potential, methods for isolating these cells from human liver, and discusses issues of their origin and heterogeneity. Human liver MSCs are a fascinating object of fundamental research with a potential for important practical applications.

Macrophages as a Cell-Based Therapy for Liver Disease

Liver failure arising from acute and chronic liver disease is an unmet clinical need that urgently requires novel therapeutic options in addition to orthotopic liver transplantation. Cell therapies offer new strategies to recover liver function through the reconstitution of healthy parenchyma and resolution of tissue pathology. Macrophages are professional phagocytes that comprise a key part of the innate immune system providing an important defense mechanism against invading pathogens. Macrophages are an inherently diverse cell type with respect to ontogeny, tissue distribution, phenotype, and function. The ability of macrophages to afford innate immunity, efficiently scavenge apoptotic/necrotic cells, and modulate local tissue microenvironment makes them an attractive cell therapy candidate for various diseases. This review aims to outline the rationale and utility of macrophages to serve as a potential cell therapy for liver disease.

Construction of multicellular aggregate by E-cadherin coated microparticles enhancing the hepatic specific differentiation of mesenchymal stem cells

The differentiation of human mesenchymal stem cells (hMSCs) into hepatocyte-like cells in vitroprovides a promising candidate for cell therapy of liver diseases, and cell aggregates have been proposed to improve the efficiency of expansion and differentiation. Previously, we engineered multicellular aggregates incorporating human E-cadherin fusion protein (hE-cad-Fc)-coated poly(lactic-co-glycolic acid) (PLGA) microparticles (hE-cad-PLGAs), and a significant improvement was obtained in both cellular proliferation of and cytokine secretion by hMSCs. In this study, hepatic differentiation of hMSCs was induced by a biomimetic microenvironment consisting of these engineered aggregates and a cocktail of specific cytokines. The ratio of hE-cad-PLGAs to hMSCs in engineered hMSCs aggregates was optimized to 1:3 for hepatic differentiation. The expressions of hepatic-specific markers were significantly promoted, and cell polarity and activated drug metabolism enzymes were established in MSC/hE-cad-PLGA aggregates compared with MSC and MSC/PLGA aggregates. Moreover, the expressions of stemness and definitive endoderm markers confirmed effectively induced endoderm differentiation in MSC/hE-cad-PLGA aggregates, which was consistent with the pattern of embryonic development. After pre-differentiation for 1 week, the MSC/hE-cad-PLGA aggregates continuously progressed the hepatic phenotype expression in healthy rat peritoneum. Therefore, the biomimetic microenvironment constructed by hE-cad-PLGAs in engineered multicellular aggregates was able to promote the process of endoderm differentiation and the subsequent hepatic differentiation of hMSCs. It would be appropriate for applied research in hepatotoxic drug screening and cell-based treatment of liver diseases. By optimizing with other cytokine cocktail, the engineered multicellular aggregates can be applied to the construction of other endoderm-derived organs. Statement of significanceThe differentiation of mesenchymal stem cells (MSCs) into hepatocyte-like cells in vitroprovides a promising for cell therapy for liver diseases, and cell aggregates have been proposed to improve the expansion and differentiation efficiency. Here, engineered multicellular aggregates were constructed by E-cadherin modified microparticles (hE-cad-PLGAs) construct a biomimetic microenvironment to promote the process of endoderm differentiation and the subsequent hepatic differentiation of hMSCs. Furthermore, after pre-differentiation for 1 week, the MSC/hE-cad-PLGA aggregates continuously progressed the hepatic phenotype expression in healthy rat peritoneum. Therefore, engineered multicellular aggregates with hE-cad-PLGAs would be appropriate for applied research in hepatotoxic drug screening and cell-based treatment of liver diseases, and provide a promising method in the construction of other endoderm-derived organs.

Distinct roles of Dlk1 isoforms in bi-potential differentiation of hepatic stem cells

BackgroundFully understanding the developmental process of hepatic stem cells (HSCs) and the mechanisms of their committed differentiation is essential for optimizing the generation of functional hepatocytes for cell therapy in liver disease. Delta-like 1 homolog (Dlk1), primarily the membrane-bound form (Dlk1M), is generally used as a surface marker for fetal hepatic stem cell isolation, while its soluble form (Dlk1S) and the functional roles of different Dlk1 isoforms in HSC differentiation remain to be investigated.MethodsHepatic spheroid-derived cells (HSDCs) were isolated from E12.5 mouse livers to obtain Dlk1+ and Dlk1−subpopulations. Colony formation, BrdU staining, and CCK8 assays were used to evaluate the cell proliferation capacity, and hepatic/cholangiocytic differentiation and osteogenesis/adipogenesis were used to assess the multipotency of the two subpopulations. Transformation of Dlk1+ cells into Dlk1− cells was detected by FACS, and the expression of Dlk1 isoforms were measured by western blot. The distinct roles and regulatory mechanisms of Dlk1 isoforms in HSC differentiation were investigated by overexpressing Dlk1M.ResultsHSDCs were capable of differentiating into liver and mesenchymal lineages, comprising Dlk1+ and Dlk1− subpopulations. Dlk1+ cells expressed both Dlk1M and Dlk1S and lost expression of Dlk1M during passaging, thus transforming into Dlk1− cells, which still contained Dlk1S. Dlk1− cells maintained a self-renewal ability similar to that of Dlk1+ cells, but their capacity to differentiate into cholangiocytes was obviously enhanced. Forced expression of Dlk1M in Dlk1− cells restored their ability to differentiate into hepatocytes, with an attenuated ability to differentiate into cholangiocytes, suggesting a functional role of Dlk1 in regulating HSC differentiation in addition to acting as a biomarker. Further experiments illustrated that the regulation of committed HSC differentiation by Dlk1 was mediated by the AKT and MAPK signaling pathways. In addition, bFGF was found to serve as an important inducement for the loss of Dlk1M from Dlk1+ cells, and autophagy might be involved.ConclusionsOverall, our study uncovered the differential expression and regulatory roles of Dlk1 isoforms in the commitment of HSC differentiation and suggested that Dlk1 functions as a key regulator that instructs cell differentiation rather than only as a marker of HSCs. Thus, our findings expand the current understanding of the differential regulation of bi-potential HSC differentiation and provide a fine-tuning target for cell therapy in liver disease.

Cytokines in adipose-derived mesenchymal stem cells promote the healing of liver disease.

Adipose-derived mesenchymal stem cells (ADSCs) are a treatment cell source for patients with chronic liver injury. ADSCs are characterized by being harvested from the patient’s own subcutaneous adipose tissue, a high cell yield (i.e., reduced immune rejection response), accumulation at a disease nidus, suppression of excessive immune response, production of various growth factors and cytokines, angiogenic effects, anti-apoptotic effects, and control of immune cells via cell-cell interaction. We previously showed that conditioned medium of ADSCs promoted hepatocyte proliferation and improved the liver function in a mouse model of acute liver failure. Furthermore, as found by many other groups, the administration of ADSCs improved liver tissue fibrosis in a mouse model of liver cirrhosis. A comprehensive protein expression analysis by liquid chromatography with tandem mass spectrometry showed that the various cytokines and chemokines produced by ADSCs promote the healing of liver disease. In this review, we examine the ability of expressed protein components of ADSCs to promote healing in cell therapy for liver disease. Previous studies demonstrated that ADSCs are a treatment cell source for patients with chronic liver injury. This review describes the various cytokines and chemokines produced by ADSCs that promote the healing of liver disease.