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Transient ischaemia and reperfusion in liver tissue induce hepatic ischaemia/reperfusion (I/R) tissue injury and a profound inflammatory response in vivo. Hepatic I/R can be classified into warm I/R and cold I/R and is characterized by three main types of cell death, apoptosis, necrosis and autophagy, in rodents or patients following I/R. Warm I/R is observed in patients or animal models undergoing liver resection, haemorrhagic shock, trauma, cardiac arrest or hepatic sinusoidal obstruction syndrome when vascular occlusion inhibits normal blood perfusion in liver tissue. Cold I/R is a condition that affects only patients who have undergone liver transplantation (LT) and is caused by donated liver graft preservation in a hypothermic environment prior to entering a warm reperfusion phase. Under stress conditions, autophagy plays a critical role in promoting cell survival and maintaining liver homeostasis by generating new adenosine triphosphate (ATP) and organelle components after the degradation of macromolecules and organelles in liver tissue. This role of autophagy may contribute to the protection of hepatic I/R‐induced liver injury; however, a considerable amount of evidence has shown that autophagy inhibition also protects against hepatic I/R injury by inhibiting autophagic cell death under specific circumstances. In this review, we comprehensively discuss current strategies and underlying mechanisms of autophagy regulation that alleviates I/R injury after liver resection and LT. Directed autophagy regulation can maintain liver homeostasis and improve liver function in individuals undergoing warm or cold I/R. In this way, autophagy regulation can contribute to improving the prognosis of patients undergoing liver resection or LT.

Organ preservation is a prerequisite for an urgent increase in the availability of organs for solid organ transplantation (SOT). An increasing amount of expanded criteria donor (ECD) organs are used clinically. Currently, the paradigm of organ preservation is shifting from simple reduction of cellular metabolic activity to maximal simulation of an ex vivo physiological microenvironment. An ideal organ preservation technique should not only preserve isolated organs but also offer the possibility of rehabilitation and evaluation of organ function prior to transplantation. Based on the fact that mesenchymal stromal cells (MSCs) possess strong regeneration properties, the combination of MSCs with machine perfusion (MP) is expected to be superior to conventional preservation methods. In recent years, several studies have attempted to use this strategy for SOT showing promising outcomes. With better organ function during ex vivo preservation and the potential of utilization of organs previously deemed untransplantable, this strategy is meaningful for patients with organ failure to help overcome organ shortage in the field of SOT.

H7N9 viruses quickly spread between mammalian hosts and carry the risk of human-to-human transmission, as shown by the 2013 outbreak. Acute respiratory distress syndrome (ARDS), lung failure, and fulminant pneumonia are major lung diseases in H7N9 patients. Transplantation of mesenchymal stem cells (MSCs) is a promising choice for treating virus-induced pneumonia, and was used to treat H7N9-induced ARDS in 2013. The transplant of MSCs into patients with H7N9-induced ARDS was conducted at a single center through an open-label clinical trial. Based on the principles of voluntariness and informed consent, 44 patients with H7N9-induced ARDS were included as a control group, while 17 patients with H7N9-induced ARDS acted as an experimental group with allogeneic menstrual-blood-derived MSCs. It was notable that MSC transplantation significantly lowered the mortality of the experimental group, compared with the control group (17.6% died in the experimental group while 54.5% died in the control group). Furthermore, MSC transplantation did not result in harmful effects in the bodies of four of the patients who were part of the five-year follow-up period. Collectively, these results suggest that MSCs significantly improve the survival rate of H7N9-induced ARDS and provide a theoretical basis for the treatment of H7N9-induced ARDS in both preclinical research and clinical studies. Because H7N9 and the corona virus disease 2019 (COVID-19) share similar complications (e.g., ARDS and lung failure) and corresponding multi-organ dysfunction, MSC-based therapy could be a possible alternative for treating COVID-19.

Acute liver injury (ALI) induced by chemicals in current experimental studies is characterized by inflammation, oxidative stress and necrosis, which can greatly influence the long‐term outcome and lead to liver failure. In liver cells, different autophagy forms envelop cytoplasm components, including proteins, endoplasmic reticulum (ER), mitochondria and lipids, and they effectively participate in breaking down the cargo enclosed inside lysosomes to replenish cellular energy and contents. In general, autophagy serves as a cell survival mechanism in stressful microenvironments, but it also serves as a destructive mechanism that results in cell death in vitro and in vivo. In experimental animals, multiple chemicals are used to mimic ALI in patients to clarify the potential pathological mechanisms and develop effective strategies in the clinic. In this review, we summarize related publications about autophagy modulation to attenuate chemically induced ALI in vitro and in vivo. We also analysed the underlying mechanisms of autophagy regulators and genetic modifications to clarify how to control autophagy to protect against chemically induced ALI in animal models. We anticipate that selectively controlling the dual effects of hepatic autophagy will help to protect against ALI in various animals, but the detailed mechanisms and effects should be determined further in future studies. In this way, we are more confident that modulating autophagy in liver regeneration can improve the prognosis of ALI.

Cell‐to‐cell communication and information exchange is one of the most important events in multiple physiological processes, including multicellular organism development, cellular function regulation, external stress response, homeostasis maintenance and tissue regeneration. New findings support the concept that subcellular component delivery may account for the beneficial effects of mesenchymal stem cell (MSC)‐based therapy‐mediated protection against acute kidney injury (AKI). Through the secretion of extracellular vesicles (EVs), formation of tunnelling nanotubes (TNTs) and development of cellular fusions, a broad range of subcellular components, including proteins, nucleic acids (mRNA and miRNA) or even organelles can be transferred from MSCs into injured renal cells, significantly promoting cell survival, favouring tissue repair and accelerating renal recovery. In this review, we outline an extensive and detailed description of the regenerative consequences of subcellular component delivery from MSCs into injured renal cells during AKI, by which the potential mechanism underlying MSC‐based therapies against AKI can be elucidated.

The liver is sensitive to pathogen-induced acute or chronic liver injury, and liver transplantation (LT) is the only effective strategy for end-stage liver diseases. However, the clinical application is limited by a shortage of liver organs, immunological rejection and high cost. Mesenchymal stromal cell (MSC)-based therapy has gradually become a hot topic for promoting liver regeneration and repairing liver injury in various liver diseases, since MSCs are reported to migrate toward injured tissues, undergo hepatogenic differentiation, inhibit inflammatory factor release and enhance the proliferation of liver cells in vivo. MSCs exert immunoregulatory effects through cell-cell contact and the secretion of anti-inflammatory factors to inhibit liver inflammation and promote liver regeneration. In addition, MSCs are reported to effectively inhibit the activation of cells of the innate immune system, including macrophages, natural killer (NK) cells, dendritic cells (DCs), monocytes and other immune cells, and inhibit the activation of cells of the adaptive immune system, including T lymphocytes, B lymphocytes and subsets of T cells or B cells. In the current review, we mainly focus on the potential effects and mechanisms of MSCs in inhibiting the activation of immune cells to attenuate liver injury in models or patients with acute liver failure (ALF), nonalcoholic fatty liver disease (NAFLD), and liver fibrosis and in patients or models after LT. We highlight that MSC transplantation may replace general therapies for eliminating acute or chronic liver injury in the near future.

Based on multiple studies in animal models, mesenchymal stem cell (MSC)‐based therapy appears to be an innovative intervention approach with tremendous potential for the management of kidney disease. However, the clinical therapeutic effects of MSCs in either acute kidney injury (AKI) or chronic kidney disease (CKD) are still under debate. Hurdles originate from the harsh microenvironment in vivo that decreases the cell survival rate, paracrine activity and migratory capacity of MSCs after transplantation, which are believed to be the main reasons for their limited effects in clinical applications. Melatonin is traditionally regarded as a circadian rhythm‐regulated neurohormone but in recent years has been found to exhibit antioxidant and anti‐inflammatory properties. Because inflammation, oxidative stress, thermal injury, and hypoxia are abnormally activated in kidney disease, application of melatonin preconditioning to optimize the MSC response to the hostile in vivo microenvironment before transplantation is of great importance. In this review, we discuss current knowledge concerning the beneficial effects of melatonin preconditioning in MSC‐based therapy for kidney disease. By summarizing the available information and discussing the underlying mechanisms, we aim to improve the therapeutic effects of MSC‐based therapy for kidney disease and accelerate translation to clinical application.

Liver diseases caused by viral infection, alcohol abuse and metabolic disorders can progress to end‐stage liver failure, liver cirrhosis and liver cancer, which are a growing cause of death worldwide. Although liver transplantation and hepatocyte transplantation are useful strategies to promote liver regeneration, they are limited by scarce sources of organs and hepatocytes. Mesenchymal stem cells (MSCs) restore liver injury after hepatogenic differentiation and exert immunomodulatory, anti‐inflammatory, antifibrotic, antioxidative stress and antiapoptotic effects on liver cells in vivo. After isolation and culture in vitro, MSCs are faced with nutrient and oxygen deprivation, and external growth factors maintain MSC capacities for further applications. In addition, MSCs are placed in a harsh microenvironment, and anoikis and inflammation after transplantation in vivo significantly decrease their regenerative capacity. Pre‐treatment with chemical agents, hypoxia, an inflammatory microenvironment and gene modification can protect MSCs against injury, and pre‐treated MSCs show improved hepatogenic differentiation, homing capacity, survival and paracrine effects in vitro and in vivo in regard to attenuating liver injury. In this review, we mainly focus on pre‐treatments and the underlying mechanisms for improving the therapeutic effects of MSCs in various liver diseases. Thus, we provide evidence for the development of MSC‐based cell therapy to prevent acute or chronic liver injury. Mesenchymal stem cells have potential as a therapeutic to prolong the survival of patients with end‐stage liver diseases in the near future.

Currently, the transplantation of mesenchymal stromal cells (MSCs) has emerged as an effective strategy to protect against tissue and organ injury. MSC transplantation also serves as a promising therapy for regenerative medicine, while poor engraftment and limited survival rates are major obstacles for its clinical application. Although multiple studies have focused on investigating chemicals to improve MSC stemness and differentiation in vitro and in vivo, there is still a shortage of effective and safe agents for MSC-based regenerative medicine. Resveratrol (RSV), a nonflavonoid polyphenol phytoalexin with a stilbene structure, was first identified in the root extract of white hellebore and is also found in the roots of Polygonum cuspidatum, and it is widely used in traditional Chinese medicine. RSV is a natural agent that possesses great therapeutic potential for protecting against acute or chronic injury in multiple tissues as a result of its antioxidative, anti-inflammatory, and anti-cancer properties. According to its demonstrated properties, RSV may improve the therapeutic effects of MSCs via enhancing their survival, self-renewal, lineage commitment, and anti-aging effects. In this review, we concluded that RSV significantly improved the preventive and therapeutic effects of MSCs against multiple diseases. We also described the underlying mechanisms of the effects of RSV on the survival, self-renewal, and lineage commitment of MSCs in vitro and in vivo. Upon further clarification of the potential mechanisms of the effects of RSV on MSC-based therapy, MSCs may be able to be more widely used in regenerative medicine to promote recovery from tissue injury.

The liver is composed of hepatocytes, cholangiocytes, Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells (HSCs) and dendritic cells; all these functional and interstitial cells contribute to the synthesis and secretion functions of liver tissue. However, various hepatotoxic factors including infection, chemicals, high‐fat diet consumption, surgical procedures and genetic mutations, as well as biliary tract diseases such as sclerosing cholangitis and bile duct ligation, ultimately progress into liver cirrhosis after activation of fibrogenesis. Melatonin (MT), a special hormone isolated from the pineal gland, participates in regulating multiple physiological functions including sleep promotion, circadian rhythms and neuroendocrine processes. Current evidence shows that MT protects against liver injury by inhibiting oxidation, inflammation, HSC proliferation and hepatocyte apoptosis, thereby inhibiting the progression of liver cirrhosis. In this review, we summarize the circadian rhythm of liver cirrhosis and its potential mechanisms as well as the therapeutic effects of MT on liver cirrhosis and earlier‐stage liver diseases including liver steatosis, nonalcoholic fatty liver disease and liver fibrosis. Given that MT is an antioxidative and anti‐inflammatory agent that is effective in eliminating liver injury, it is a potential agent with which to reverse liver cirrhosis in its early stage.

Aim Haemoglobin (Hb) variability has been reported to be associated with mortality in dialysis patients in some but not all studies. We aimed to establish the prognostic significance of Hb variability with all‐cause mortality in haemodialysis patients through this meta‐analysis. Methods The Medline, Embase, Cochrane Library and Web of Science databases were searched for studies assessing the association between Hb variability and all‐cause mortality in haemodialysis patients after adjustment for other covariates. Results We included three studies of five cohorts with a total of 262 641 patients. Forest plots showed that the combined hazard ratio for all‐cause mortality was 1.09 (95% CI = 1.01–1.08; P = 0.03) per 1 g/dL increase in Hb variability. Conclusion Based on the current evidence, our meta‐analysis found an association between Hb variability and all‐cause mortality in patients receiving haemodialysis therapy., SUMMARY AT A GLANCE Three studies of five cohorts with a total of 262 641 patients showed a combined hazard ratio for all‐cause mortality in HD patients to be 1.09 (95% CI = 1.01–1.08; P = 0.03) per 1 g/dL increase in the haemoglobin level. A significant heterogeneity exists between the studies.

Although the liver is the only organ with regenerative capacity, various injury factors induce irreversible liver dysfunction and end‐stage liver disease. Liver resection and liver transplantation (LT) are effective treatments for individuals with liver failure, liver cirrhosis and liver cancers. The remnant or transplanted liver tissues will undergo hepatic ischaemia/reperfusion (IR), which leads to oxidative stress, inflammation, immune injury and liver damage. Moreover, systemic ischaemia induced by trauma, stroke, myocardial ischaemia, haemorrhagic shock and other injury factors also induces liver ischaemia/reperfusion injury (IRI) in individuals. Hepatic IRI can be divided into warm IRI, which is induced by liver surgery and systemic ischaemia, and cold IRI, which is induced by LT. Multiple studies have shown that melatonin (MT) acts as an endogenous free radical scavenger with antioxidant capacity and is also able to attenuate hepatic IRI via its anti‐inflammatory and antiapoptotic capacities. In this review, we discuss the potential mechanisms and current strategies of MT administration in liver surgery for protecting against warm or cold hepatic IRI. We highlight strategies to improve the efficacy and safety of MT for attenuating hepatic IRI in different conditions. After the potential mechanisms underlying the interactions between MT and other important cellular processes during hepatic IR are clarified, more opportunities will be available to use MT to treat liver diseases in the future., Melatonin serves as an endogenous free radical scavenger with antioxidation capacity, and it is also able to attenuate hepatic ischaemia/reperfusion injury via its anti‐inflammation, and antiapoptotic capacities.

Objective The aim of this meta-analysis was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) versus traditional regimens for induction therapy in kidney transplantation (KT), especially the safety of MSC infusion, practicability of MSCs as induction therapy agents, and posttransplant complications. Methods PubMed, Embase, EBSCO, Ovid, and the Cochrane Library were searched for prospective clinical trials that compared MSCs with traditional regimens for induction therapy in KT. Results Four trials were included, including a total of 197 patients. The pooled results revealed that MSC therapy had a lower 1-year infection rate than did the traditional therapies (RR = 0.65, 95% CI: 0.46–0.9, P = 0.01). There were no significant differences between the two protocols regarding the 1-year acute rejection (AR) rate (RR = 0.77, 95% CI: 0.41–1.45, P = 0.42), 1-year graft survival rate (RR = 0.99, 95% CI: 0.95–1.03, P = 0.74), delayed graft function (DGF) rate (RR = 0.54, 95% CI: 0.21–1.38, P = 0.2) and renal graft function at 1 month (MD = −1.56, 95% CI: − 14.2–11.08, p = 0.81), 3 months (MD = 0.15, 95% CI: − 5.63–5.93, p = 0.96), 6 months (MD = − 1.95, 95% CI: − 9.87–5.97, p = 0.63), and 12 months (MD = − 1.13, 95% CI: − 7.16–4.89, p = 0.71) postsurgery. Subgroup analysis demonstrated that the 1-year AR rate, 1-year graft survival rate, DGF rate, and renal graft function at 12 months postsurgery did not significantly differ between the low-dose calcineurin inhibitor (CNI) group and the standard-dose CNI group, indicating the potential benefits of successful CNI sparing in combination with MSC treatment. Moreover, when MSCs were applied as an alternative therapy rather than an additional therapy or allogeneic MSCs were utilized instead of autologous MSCs, all of the outcomes mentioned above were comparable. Conclusion Induction therapy with MSCs is safe and has similar immune response modulation effects to those of traditional regimens in the short term in KT recipients. However, regarding the long-term effects, as suggested by the 1-year infection rate and the potential of CNI sparing, MSC therapy has significant advantages. However, these advantages should be further verified in more well-designed, multicenter randomized controlled trials (RCTs) with large sample sizes and long follow-up periods.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by recurrent episodes of manic/hypomanic or depressive symptoms and euthymic periods, with some patients suffering a gradual deterioration of illness and consequent cognitive deficits during the late stage. Migraine is a disease generally without abnormal medical examinations, neurological examinations or laboratory studies, and the diagnosis is made based on the retrospective demonstration of headache features and groupings of disease-associated symptoms. The epidemiology of comorbid BD and migraine is high and it is obligatory to find effective treatments to improve the prognosis. Recent investigations demonstrated that the close relationship between BD and migraine significantly increased the rapid cycling rates of both BD and migraine in patients. Although the detailed mechanism is complex and largely unclear in comorbid BD and migrain, genetic factors, neurotransmitters, altered signaling pathways, disturbances of inflammatory cytokines, and mitochondrial dysfunction are risk factors of BD and migraine. Particularly these two diseases share some overlapping mechanisms according to previous studies. To this end, we call for further investigations of the potential mechanisms, and more efforts are underway to improve the treatment of people with comorbid BD and migraine. In this review, we provide an overview of the potential mechanisms in patients with BD or migraine and we further discuss the treatment strategies for comorbid BD and migraine and it is obligatory to find effective treatments to improve the prognosis. This work will provide insights for us to know more about the mechanisms of comorbid BD and migraine, provides new therapeutic targets for the treatment and give clinicians some guidance for more appropriate and beneficial treatment.

Curcumin is a type of plant polyphenol extracted from Curcuma longa L. rhizome, which demonstrates antitumor activity in breast cancer cells in vitro. To investigate the combined effect and possible mechanism of curcumin and glucose-gold nanoparticles (Glu-GNPs), the radiosensitivity of breast carcinoma xenografts was assessed in nude mice. MDA-MB-231 cells labeled with firefly luciferase were inoculated into the mammary fatty pads of nude mice to establish a transplantation tumor model of human breast cancer. The tumor-bearing mice were treated with different drugs (curcumin, Glu-GNPs, and cisplatin) for 3 weeks prior to radiotherapy. The body weights and tumor volumes of the mice were measured in regular intervals. Tumor bioluminescence intensity was determined in real-time using an in vivo bioluminescence imaging system to monitor tumor growth. Transplanted tumor tissue samples were taken for hematoxylin and eosin (HE) staining, and the expression of VEGF, HSP90, HIF-1α, and MMP9 was evaluated via reverse transcription-quantitative PCR or immunohistochemistry. The results revealed that the breast tumor-bearing nude mouse model was successfully established, as evidenced by a stable expression of luciferase. Curcumin inhibited the growth of tumors without causing significant weight loss in mice. Furthermore, additive inhibition was demonstrated when curcumin was administered in combination with Glu-GNPs and irradiation. Tumor bioluminescence intensity was decreased in the model group following curcumin, Glu-GNPs, and irradiation treatment. HE staining demonstrated that transplanted tumors were malignant, with necrotic tissue exhibited centrally. It was concluded that curcumin administered in combination with Glu-GNPs and X-ray irradiation could reduce the protein expression of VEGF, HSP90, HIF-1α, and MMP9 in tumor tissue when compared with the model group. Curcumin and Glu-GNPs administered with X-ray irradiation significantly inhibited tumor growth and induced radiosensitivity, which may be associated with the inhibition of angiogenesis in tumor tissue.

Liver dysfunction and failure can have diverse etiologies and finally result in irreversible liver failure which is life-threatening all over the world. Although liver transplantation (LT) becomes the optimal treatment for acute liver failure, chronic liver failure, and hereditary metabolic liver diseases, the application of LT is inhibited by the scarce of liver donors, transplant complications, and expensive costs. Then cell transplantation has opened up a new field for LT, the source of liver cells and dysfunction of cryopreserved hepatocytes limit the widespread use of primary hepatocyte transplantation. Then, various kinds of cells including heterogeneous hepatocytes, tumor-derived hepatocytes, immortalized hepatocytes, embryonic stem cells (ESCs), and adult stem cells are emerging as the alternatives for hepatocyte transplantation. This chapter will focus on the cell sources of the transplanted cells, cell isolation, cell culture, transplantation routes, clinical application, and prospects of cell transplantation. We believed that after accelerating the development of cell transplantation-related techniques (in vitro cell culture, cryopreservation, and transplantation route) and clarifying the immunology and molecular biology of cell transplantation at the molecular level, there will eventually be a wider range of cell transplantation options for the treatment of human liver diseases.

Ammonia is thought to be central to the pathogenesis of hepatic encephalopathy (HE), but its prognostic role in acute-on-chronic liver failure (ACLF) is still unknown. We aimed to determine the association between serum ammonia level and short-term prognosis in ACLF. Furthermore, we performed an in-depth evaluation of the independent effect of serum ammonia level on the short-term prognosis of hepatitis B virus (HBV) reactivation-induced ACLF patients. We identified 174 patients as part of prospective observational studies in patients with ACLF. Plasma ammonia levels were measured on admission, and several prognostic scores were used to determine the prognostic effect of ammonia. The 28-day patient survival was determined. Receiver operating characteristic analysis was used to identify the cut-off points for ammonia values, and multivariable analysis was performed using the Cox proportional hazard regression model. Plasma ammonia was significantly higher in nonsurvivors (83.53 ± 43.78 versus 67.13 ± 41.77 µmol/L, P = 0.013), and ACLF patients with hyperammonemia had significantly higher 28-day mortality than those without hyperammonemia. Ammonia was also closely related to ACLF grade (P

Breast cancer is the most common type of cancer among women worldwide. The Hippo signaling pathway is strongly associated with cell proliferation, migration, invasion, metastasis and resistance to breast cancer treatment. The upstream factors involved in the Hippo signaling pathway, including mammalian Ste20 kinases 1/2, large tumor suppressor kinases 1/2 and transcription coactivator Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), have been extensively studied as they are considered therapeutic targets for breast cancer. Recently, it has been suggested that the transcriptional enhancer factor domain (TEAD) family of transcription factors, particularly TEAD4, plays an important role in breast cancer. TEADs interact with YAP/TAZ to act as transcription factors. Notably, recent studies have demonstrated that TEAD4 may also function in a YAP/TAZ-independent manner and serve as a prognostic marker for breast cancer. The present review summarizes the current research on the effect of the aberrant activation of the Hippo signaling pathway on breast cancer progression. Furthermore, the latest advances on the role of the TEAD family in breast cancer are highlighted, and the role of TEAD4 as a potential target for therapeutic intervention in breast cancer is discussed.

Various hepatoxic factors, such as viruses, drugs, lipid deposition, and autoimmune responses, induce acute or chronic liver injury, and 3.5% of all worldwide deaths result from liver cirrhosis, liver failure, or hepatocellular carcinoma. Liver transplantation is currently limited by few liver donors, expensive surgical costs, and severe immune rejection. Cell therapy, including hepatocyte transplantation and stem cell transplantation, has recently become an attractive option to reduce the overall need for liver transplantation and reduce the wait time for patients. Recent studies showed that mesenchymal stem cell (MSC) administration was a promising therapeutic approach for promoting liver regeneration and repairing liver injury by the migration of cells into liver sites, hepatogenic differentiation, immunoregulation, and paracrine mechanisms. MSCs secrete a large number of molecules into the extracellular space, and soluble proteins, free nucleic acids, lipids, and extracellular vesicles (EVs) effectively repair tissue injury in response to fluctuations in physiological states or pathological conditions. Cell-free-based therapies avoid the potential tumorigenicity, rejection of cells, emboli formation, undesired differentiation, and infection transmission of MSC transplantation. In this review, we focus on the potential mechanisms of MSC-based cell-free strategies for attenuating liver injury in various liver diseases. Secretome-mediated paracrine effects participate in the regulation of the hepatic immune microenvironment and promotion of hepatic epithelial repair. We look forward to completely reversing liver injury through an MSC-based cell-free strategy in regenerative medicine in the near future.

Different hepatoxic factors cause irreversible liver injury, leading to liver failure, cirrhosis, and cancer in mammals. Liver transplantation is the only effective strategy, which can improve the prognosis of patients with end-stage liver diseases, but it is limited by liver donor shortage, expensive costs, liver graft rejection and dysfunction, and recurring liver failure. Recently, mesenchymal stromal cells (MSCs) isolated from various tissues are regarded as the main stem cell type with therapeutic effects in liver diseases because of their hepatogenic differentiation, anti-inflammatory, immuoregulatory, anti-apoptotic, antifibrotic, and antitumor capacities. To further improve the therapeutic effects of MSCs, multiple studies showed that genetically engineered MSCs have increased regenerative capacities and are able to more effectively inhibit cell death. Moreover, they are able to secrete therapeutic proteins for attenuating liver injury in liver diseases. In this review, we mainly focus on gene overexpression for reprogramming MSCs to increase their therapeutic effects in treating various liver diseases. We described the potential mechanisms of MSCs with gene overexpression in attenuating liver injury, and we recommend further expansion of experiments to discover more gene targets and optimized gene delivery methods for MSC-based regenerative medicine. We also discussed the potential hurdles in genetic engineering MSCs. In conclusion, we highlight that we need to overcome all scientific hurdles before genetically modified MSC therapy can be translated into clinical practices for patients with liver diseases.

Breast cancer is the first cause of cancer death in women all over the world. And the morbidity of breast cancer has been increasing in recent years. Nowadays, the treatment of breast cancer is still a problem. Radiotherapy resistance is one of the important factors leading to poor prognosis of clinical treatment. Curcumin, a plant polyphenol from Curcuma longa, has antitumor activity and inhibition of tumor recurrence and metastasis. However, the influence of curcumin on radiosensitivity of breast carcinoma xenografts, the synergistic effect and possible mechanism of curcumin and Glucose-Gold nanoparticles (Glu-GNPs) in nude mice in vivo need to be further explored. The model of transplanted tumor in nude mice was established and sensitized by intravenous injection of curcumin and Glu-GNPs. The results showed that curcumin can significantly inhibit the growth of tumor, and has no obvious effect on the body weight of nude mice, and Curcumin, Glu-GNPs and X-ray irradiation treatment alone or in combination could reduce the expression of VEGF and HSP90 mRNA and protein compared with model group in tumor tissue. The inhibition of irradiation resistance may be related to inhibiting the synthesis of VEGF and HSP90. This study suggested that curcumin and Glu-GNPs have the radiosensitization effect in vivo, which provides an experimental basis for the clinical development of green radiosensitizers.

The inevitable side effects caused by lifelong immunosuppressive agents in kidney transplantation patients spurred the exploration of novel immunosuppressive strategies with definite curative effects and minimal adverse effects. Mesenchymal stem cells (MSCs) have become a promising candidate due to their role in modulating the immune system. Encouraging results obtained from experimental models have promoted the translation of this strategy into clinical settings. However, the demonstration of only marginal or transient benefits by several recent clinical controlled studies has made physicians hesitant to adopt the routine utilization of this procedure in clinical settings. Impaired MSC function after infusion in vivo was thought to be the main reason for their limited effects. For this reason, some preconditioning methods were developed. In this review, we aim to outline the current understanding of the preconditioning methods being explored as a strategy to improve the therapeutic effects of MSCs in kidney transplantation and promote its clinical translation.

Acetaminophen (APAP)-induced injury is a common clinical phenomenon that not only occurs in a dose-dependent manner but also occurs in some idiosyncratic individuals in a dose-independent manner. APAP overdose generally results in acute liver injury via the initiation of oxidative stress, endoplasmic reticulum (ER) stress, autophagy, liver inflammation, and microcirculatory dysfunction. Liver transplantation is the only effective strategy for treating APAP-induced liver failure, but liver transplantation is inhibited by scarce availability of donor liver grafts, acute graft rejection, lifelong immunosuppression, and unbearable costs. Currently, N-acetylcysteine (NAC) effectively restores liver functions early after APAP intake, but it does not protect against APAP-induced injury at the late stage. An increasing number of animal studies have demonstrated that mesenchymal stem cells (MSCs) significantly attenuate acute liver injury through their migratory capacity, hepatogenic differentiation, immunoregulatory capacity, and paracrine effects in acute liver failure (ALF). In this review, we comprehensively discuss the mechanisms of APAP overdose-induced liver injury and current therapies for treating APAP-induced liver injury. We then comprehensively summarize recent studies about transplantation of MSC and MSC derivatives for treating APAP-induced liver injury. We firmly believe that MSCs and their derivatives will effectively promote liver regeneration and liver injury repair in APAP overdose-treated animals and patients. To this end, MSC-based therapies may serve as an effective strategy for patients who are waiting for liver transplantation during the early and late stages of APAP-induced ALF in the near future.

Breast cancer stem cells are an important cause of radiotherapy resistance in the clinical treatment of breast cancer patients. How to target breast cancer stem cells is the key to improving the efficacy of breast cancer radiotherapy. We proposed for the first time that curcumin combined with glucose nanogold particles (Glu-GNPs) targeted breast cancer stem cells to reduce radiotherapy resistance, which can significantly enhance the apoptosis level of MCF-7 and MDA-MB-231 breast cancer stem-like cells (BCSCs) after radiotherapy and antiproliferation and colony-forming. Under simulated hypoxic conditions, curcumin combined with Glu-GNPs can significantly improve the ROS level of MCF-7 and MDA-MB-231 mammospheres; reduce the expression of HIF-1α and HSP90, thereby inhibiting the tumor cells’ own stress ability; promote the apoptosis of tumor stem cells; and enhance the sensitivity of radiotherapy. The current results indicate that the combination of curcumin and Glu-GNPs has great potential to relieve tumor hypoxia and increase radiosensitivity on BCSCs, providing scientific research data for developing a novel radiosensitizer with high efficiency and low toxicity.

Ethnopharmacological relevance In traditional Chinese medicine, there is a long history that curcuma longa L is used to treat distending pain of chest and belly, arthralgia of shoulder and arm aggravated by cold. Traditional Chinese medicine holds that breast cancer is caused by cold congelation, stagnation of qi and blood stasis. It is usually treated with some pungent and warm Chinese herbs, such as Curcuma longaL and Curcuma zedoaria (Christm.) Rosc, which are effective in promoting blood circulation for removing blood stasis, activating qi-flowing and relieving pain. Curcumin, a polyphenolic compound, is the main pharmacological component extracted from the rhizome of Curcuma longaL. Modern pharmacological studies have found that curcumin has many kinds of pharmacological activities of anti-inflammatory, anti-tumor, anti-angiogenesis, anti-metastasis and anti-multidrug resistance. Aim of the study To explore the mechanism of curcumin and Glioma-associated oncogene homolod-1 (Gli1) on invasion and metastasis of triple negative breast cancer (TNBC) cells through the Hedgehog (Hh)/Gli signaling pathway. Material and methods The effect of curcumin on TNBC cells was detected by colony formation, wound healing and transwell assay. Breast cancer stem cells (BCSCs) were cultured in serum-free medium and its stemness was detected by flow cytometry and subcutaneous xenografted tumor assay. The formation of mammospheres was used to detect the effect of curcumin and GANT61(Gli inhibitor)on the formation ability of BCSCs. Gli1 overexpressed was conducted in MDA-MB-231 cells by lentivirus vector HBLV-h-Gli1-3xflag-ZsGreen-PURO. RT-qPCR and western blot were detected the mRNA and protein level of genes of Hh pathway, Epithelial-mesenchymal transition (EMT) and stemness. The nuclear localization and expression of Gli1 was observed by laser confocal microscope scanning. Co-IP was investigated the key genes interacted with Gli1. Results The abilities of proliferation, invasion, migration and the formation of mammospheres in TNBC cells were inhibited by curcumin. Furthermore, curcumin reduced the invasion and migration abilities in stable Gli1-overexpressing MDA-MB-231 cell. Moreover, curcumin down-regulated the expression of genes related Hh pathway, EMT and stemness in MDA-MB-231 mammospheres. Observation of laser confocal microscope showed that Gli1 were expressed mainly in nucleus in MDA-MB-231 adherent cells and completely in nucleus in BCSCs, which was significantly reduced in the nucleus and cytoplasm after curcumin treatment. Besides, our results suggested that vimentin was interacted with Gli1. Conclusions Curcumin can inhibit the proliferation and metastasis of TNBC cells, EMT and characteristics of BCSC by Hedgehog/Gli1 pathway.

Acute kidney injury (AKI) is a common, severe emergency case in clinics, with high incidence, significant mortality and increased costs. Despite development in the understanding of its pathophysiology, the therapeutic choices are still confined to dialysis and renal transplantation. Considering their antiapoptotic, immunomodulatory, antioxidative and pro‐angiogenic effects, mesenchymal stem cells (MSCs) may be a promising candidate for AKI management. Based on these findings, some clinical trials have been performed, but the results are contradictory (NCT00733876, NCT01602328). The low engraftment, poor survival rate, impaired paracrine ability and delayed administration of MSCs are the four main reasons for the limited clinical efficacy. Investigators have developed a series of preconditioning strategies to improve MSC survival rates and paracrine ability. In this review, by summarizing these encouraging studies, we intend to provide a comprehensive understanding of various preconditioning strategies on AKI therapy and improve the prognosis of AKI patients by regenerative medicine.

Accurate individual exposure assessment to particulates in complex urban environments requires maps of PM2.5 concentration at high spatiotemporal resolution. Previous empirical researches of PM2.5 mapping usually have ignored the contextual influences of associated factors on pollution variation. This study presents a new thinking about spatial prediction of PM2.5 pollution based on the pollution scene assumption. Methodologically, pollution scenes are areas exert contextual influences on the spatiotemporal variety of air pollution and can be expressed by urban microenvironment dependence and temporal nonstationarity. Taking Changsha, China as a case, a two-stage modelling strategy of geographically weighted regression kriging (GWRK) was developed to validate the assumption based on a high-density sampling campaign and a fine-scale, manually interpreted urban microenvironment map. Our results confirm the potential existence of urban air pollution scene. PM2.5 concentration varies between urban microenvironments; pollution scene based GWRK is effective for high resolution mapping of PM2.5 concentration at the hourly scale and depicts more detailed spatial variations than traditional GWR in this study. This assumption and modelling strategy provide a promising way for mapping urban air pollution at high resolution which will further benefits works on exposure assessment and risk avoidance at fine scales.

The liver, the largest organ with multiple synthesis and secretion functions in mammals, consists of hepatocytes and Kupffer, stem, endothelial, stellate and other parenchymal cells. Because of early and extensive contact with the external environment, hepatic ischaemia reperfusion (IR) may result in mitochondrial dysfunction, autophagy and apoptosis of cells and tissues under various pathological conditions. Because the liver requires a high oxygen supply to maintain normal detoxification and synthesis functions, it is extremely susceptible to ischaemia and subsequent reperfusion with blood. Consequently, hepatic IR leads to acute or chronic liver failure and significantly increases the total rate of morbidity and mortality through multiple regulatory mechanisms. An increasing number of studies indicate that mitochondrial structure and function are impaired after hepatic IR, but that the health of liver tissues or liver grafts can be effectively rescued by attenuation of mitochondrial dysfunction. In this review, we mainly focus on the subsequent therapeutic interventions related to the conservation of mitochondrial function involved in mitigating hepatic IR injury and the potential mechanisms of protection. Because mitochondria are abundant in liver tissue, clarification of the regulatory mechanisms between mitochondrial dysfunction and hepatic IR should shed light on clinical therapies for alleviating hepatic IR‐induced injury.

Mitochondria take part in a network of cellular processes that regulate cell homeostasis. Defects in mitochondrial function are key pathophysiological changes during acute kidney injury (AKI). Mesenchymal stem cells (MSCs) have shown promising regenerative effects in experimental AKI models, but the specific mechanism is still unclear. Some studies have demonstrated that MSCs are able to target mitochondrial dysfunction during AKI. In this review, we summarize these articles, providing an integral and updated view of MSC therapy targeting mitochondrial dysfunction during AKI, which is aimed at promoting the therapeutic effect of MSCs in AKI patients.

In mammals, a basal level of autophagy, a self-eating cellular process, degrades cytosolic proteins and subcellular organelles in lysosomes to provide energy, recycles the cytoplasmic components, and regenerates cellular building blocks; thus, autophagy maintains cellular and tissue homeostasis in all eukaryotic cells. In general, adaptive autophagy increases when cells confront stressful conditions to improve the survival rate of the cells, while destructive autophagy is activated when the cellular stress is not manageable and elicits the regenerative capacity. Hypoxia-reoxygenation (H/R) injury and ischemia-reperfusion (I/R) injury initiate excessive autophagy and endoplasmic reticulum (ER) stress and consequently induce a string of damage in mammalian tissues or organs. Mesenchymal stem cell (MSC)-based therapy has yielded promising results in repairing H/R- or I/R-induced injury in various tissues. However, MSC transplantation in vivo must overcome the barriers including the low survival rate of transplanted stem cells, limited targeting capacity, and low grafting potency; therefore, much effort is needed to increase the survival and activity of MSCs in vivo. Modulating autophagy regulates the stemness and the anti-oxidative stress, anti-apoptosis, and pro-survival capacity of MSCs and can be applied to MSC-based therapy for repairing H/R- or I/R-induced cellular or tissue injury.

Stem cell-based therapy appears to be a promising new candidate for acute kidney injury (AKI) management. Traditionally, it has been accepted that the mechanism underlying the regenerative effect of stem cells is based on their paracrine/endocrine activity, including release of bioactive factors that act on injured renal cells and presentation of proangiogenic, antiapoptotic, antioxidative, and immunomodulatory effects. Recently, multiple studies have confirmed that extracellular vesicles (EVs) are a kind of vesicle rich in a broad variety of biologically active molecules, including lipids, proteins, and, in particular, nucleic acids. EVs are able to transfer genetic information to target cells, alter target gene regulatory networks, and exert biological effects. Stem cell-derived EVs (SC-EVs) are emerging as potent genetic information sources that deliver mRNAs and miRNAs to injured renal cells and exert renoprotective effects during AKI. On the other hand, EVs originating from injured renal cells also contain genetic information that is believed to be able to influence phenotypic and functional changes in stem cells, favoring renal recovery. In this review, we summarize studies providing evidence of genetic communication during the application of stem cells in preclinical AKI models, aiming to clarify the mechanism and describe the therapeutic effects of stem cell-based therapy in AKI patients.

Although stem cells have emerged as promising sources for regenerative medicine, there are many potential safety hazards for their clinical application, including tumorigenicity, an availability shortage, senescence, and sensitivity to toxic environments. Mesenchymal stem cells (MSCs) have various advantages compared to other stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs); thus, MSCs have been intensely investigated in recent studies. However, they are placed in a harsh environment after isolation and transplantation, and the adverse microenvironment substantially reduces the viability and therapeutic effects of MSCs. Intriguingly, melatonin (MT), which is primarily secreted by the pineal organ, has been found to influence the fate of MSCs during various physiological and pathological processes. In this review, we will focus on the recent progress made regarding the influence of MT on stem cell biology and its implications for regenerative medicine. In addition, several biomaterials have been proven to significantly improve the protective effects of MT on MSCs by controlling the release of MT. Collectively, MT will be a promising agent for enhancing MSC activities and the regenerative capacity via the regulation of reactive oxygen species (ROS) generation and the release of immune factors in regenerative medicine.

BackgroundInterleukin (IL)-6/signal transducers and activators of transcription 3 (STAT3) signaling plays an important role in the development of colitis-associated colorectal cancer (CAC). The mechanism of CAC formation remains unclear, and the relationship between miRNAs and the IL-6/STAT3 signaling pathway in the development of CAC is not well understood. In this study, we investigated the relationship between miR-29a-5p and the IL-6/STAT3 signaling pathway in the development of CAC and alterations in 10-11 translocations (TETs) regulated by this network.MethodsmiR-29a-5p was screened in a CAC mouse model by high-throughput microarray analysis and investigated in human colorectal cancer tissue samples and colon cell lines by quantitative reverse transcription polymerase chain reaction (Q-RTPCR). The expression of miR-29a and TETs was detected by Q-RTPCR, and the expression of STAT3/P-STAT3 and TET3 was detected via Western blot assay. The expression of TET1 and 5-hydroxymethylcytosine (5hmC) was detected through immunofluorescence.ResultsOur results showed that miR-29a-5p was significantly upregulated and was accompanied by STAT3 activation in the colon tissues of CAC mouse and human colorectal cancer tissues, as compared with normal colon tissues. In contrast, the levels of TETs and 5hmC were decreased. In vitro, overexpression of miR-29a-5p in colonic cell lines (HCT-116 and IEC-6) and RAW264.7 cells increased STAT3 expression, but decreased that of TET3, TET1, and 5hmC. miR-29a-5p downregulation in HCT-116 and IEC-6 cell lines could rescue the expression of STAT3 and TET3. Notably, STAT3 activation induced by IL-6 upregulated miR-29a-5p expression and reduced TET expression in vitro, although STAT3 inhibitor treatment downregulated miR-29a-5p expression, which was induced by IL-6.ConclusionsOur studies showed that tumor development occurred with inflammation. The miR-29a-5p/STAT3 signaling axis could play an important role in the development of CAC, and the miR-29a-5p/STAT3 positive feedback loop may amplify the effects of inflammation, lead to decreased levels of TET and 5hmC, and eventually lead to the development of CAC.

After the death of large numbers of cells in liver tissue is triggered by various hepatotoxic factors, intimidating and life-threatening acute liver failure (ALF) can develop with high mortality and expensive costs. Although liver transplantation and hepatocyte transplantation have become substitutes for improving liver regeneration, their applications are inhibited by scarce tissue and cell resources. Therefore, the transplantation of mesenchymal stromal cells (MSCs) and their derivatives including hepatocyte-like cells (HLCs), conditioned medium (CM), and exosomes (Ex) can help alleviate liver injury in ALF individuals or animal models via engraftment into liver tissue, hepatogenic differentiation, the promotion of host hepatocyte proliferation, the secretion of anti-inflammatory factors and antioxidants, and the enhancement of liver regeneration in vivo. In addition, biomaterial scaffolds protect MSCs against a harsh microenvironment in vitro and in vivo, in addition to providing physical and directional support for liver regeneration. In this review, we aimed to discuss the underlying mechanisms and therapeutic effects of MSCs and their derivatives on rescuing ALF animal models according to current studies. Further breakthroughs are required to establish safer, more stable, and more effective stem cell-based therapy in regenerative medicine for repairing liver injury, thus reducing the morbidity and mortality of ALF in the near future.

Although systematic therapeutic approaches have reduced cancer-associated mortality, metastatic breast cancer can still evade therapy, particularly triple-negative breast cancer, which remains associated with high rates of cancer metastasis and has the worst clinical prognosis. Lipocalin 2 (LCN2) is a secreted glycoprotein that transports small lipophilic ligands. Its abnormal expression serves critical roles in the epithelial-to-mesenchymal transition process, angiogenesis, and cell migration and invasion in breast cancer. Notably, LCN2 functions as an initiator of carcinogenesis and metastasis by involving multiple signaling pathways. The present review aims to summarize research findings on the abnormal expression of LCN2 in breast cancer progression. Furthermore, the review highlights the latest developments of potential LCN2-targeting agents and proposed LCN2-associated molecular mechanisms with regard to breast cancer invasion and metastasis.

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.

Acute kidney injury (AKI) remains a worldwide public health issue due to its increasing incidence, significant mortality, and lack of specific target-orientated therapy. Developments in mesenchymal stem cell (MSC) research make MSCs a promising candidate for AKI management but relevant clinical trials show confusing results (NCT00733876, NCT01602328). One primary cause of the limited therapeutic effect may result from poor engraftment of transplanted cells. To solve this problem, investigators have developed a series of preconditioning strategies to improve MSC engraftment in animal AKI models. In this review, we summarize these previous studies, providing an integrated and updated view of different preconditioning strategies aimed at promoting the therapeutic effect of MSCs in AKI patients.

BACKGROUND HBV-related acute-on-chronic liver failure (HBV-ACLF) deteriorates rapidly in the short term, which necessitates accurate initial clinical decision making. AIMS To develop a novel prognostic score for patients with HBV-ACLF and clarify the role of thyroid hormones in HBV-ACLF. METHODS A retrospective cohort of 635 HBV-ACLF patients was enrolled to develop and validate a novel prognostic score for HBV-ACLF. Additionally, a cross-sectional cohort (n = 199) and a prospective longitudinal HBV-ACLF cohort (n = 56) were recruited to clarify the association between thyroid hormone status and the 30-day mortality of HBV-ACLF. RESULTS HINT, a novel prognostic score based on hepatic encephalopathy, INR, neutrophil count, and thyroid-stimulating hormone (TSH) using the deriving cohort (n = 426), was significantly higher in non-survivors than survivors (1.17 ± 2.38 vs -1.87 ± 1.26, P

Background Curcumin is a polyphenolic compound with potent chemopreventive and anti-cancer efficacy. Purpose To explore the potential anti-metastasis efficacy of curcumin in breast cancer stem-like cells (BCSCs), which are increasingly considered to be the origin of the recurrence and metastasis of breast cancer. Methods A CCK8 assay was performed to evaluate cell viability, and a colony formation assay was conducted to determine cell proliferation in MCF-7 and MDA-MB-231 adherent cells. Transwell and wound healing assays were used to detect the effect of curcumin on cell migration and invasion in MDA-MB-231 cells. Mammospheres were cultured with serum free medium (SFM) for three generations and the BCSC surface marker CD44+CD24−/low subpopulation was measured by flow cytometry. Mammosphere formation and differentiation abilities were determined after cell treatment with curcumin. Then, a reverse transcription-quantitative polymerase chain reaction assay was conducted to detect the relative mRNA level of epithelial-mesenchymal transition (EMT) marker genes and western blot analysis was performed to determine the protein expression of stem cell genes in mammospheres treated with curcumin. Results Curcumin exhibited anti-proliferative and colony formation inhibiting activities in both the MCF-7 and MDA-MB-231 cell lines. It also suppressed the migration and invasion of MDA-MB-231 cells. The CD44+CD24−/low subpopulation was larger in mammospheres when MCF-7 and MDA-MB-231 adherent cells were cultured with SFM. Further studies revealed that curcumin inhibited mammosphere formation and differentiation abilities. Moreover, curcumin down-regulated the mRNA expression of Vimentin, Fibronectin, and β-catenin, and up-regulated E-cadherin mRNA expression levels. Western blot analysis demonstrated that curcumin decreased the protein expression of stem cell genes including Oct4, Nanog and Sox2. Conclusion The results of the present study suggest that the inhibitor effects of curcumin on breast cancer cells may be related to resistance to cancer stem-like characters and the EMT process. These data indicate that curcumin could function as a type of anti-metastasis agent for breast cancer.

The conversion of somatic cells to hepatocytes has fundamentally re-shaped traditional concepts regarding the limited resources for hepatocyte therapy. With the various induced pluripotent stem cell (iPSC) generation routes, most somatic cells can be effectively directed to functional stem cells, and this strategy will supply enough pluripotent material to generate promising functional hepatocytes. However, the major challenges and potential applications of reprogrammed hepatocytes remain under investigation. In this review, we provide a summary of two effective routes including direct reprogramming and indirect reprogramming from somatic cells to hepatocytes and the general potential applications of the resulting hepatocytes. Through these approaches, we are striving toward the goal of achieving a robust, mature source of clinically relevant lineages.

The shortage of liver donors is a major handicap that prevents most patients from receiving liver transplantation and places them on a waiting list for donated liver tissue. Then, primary hepatocyte transplantation and bioartificial livers have emerged as two alternative treatments for these often fatal diseases. However, another problem has emerged. Functional hepatocytes for liver regeneration are in short supply, and they will dedifferentiate immediatelyin vitroafter they are isolated from liver tissue. Alternative stem-cell-based therapeutic strategies, including hepatic stem cells (HSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), are more promising, and more attention has been devoted to these approaches because of the high potency and proliferation ability of the cells. This review will focus on the general characteristics and the progress in hepatic differentiation of adult somatic stem cells and extraembryonic stem cellsin vitroandin vivofor the treatment of end stage liver diseases. The hepatic differentiation of stem cells would offer an ideal and promising source for cell therapy and tissue engineering for treating liver diseases.

Various diseases and toxic factors easily impair cellular and organic functions in mammals. Organ transplantation is used to rescue organ function, but is limited by scarce resources. Mesenchymal stem cell (MSC)‐based therapy carries promising potential in regenerative medicine because of the self‐renewal and multilineage potency of MSCs; however, MSCs may lose biological functions after isolation and cultivation for a long time in vitro. Moreover, after they are injected in vivo and migrate into the damaged tissues or organs, they encounter a harsh environment coupled with death signals due to the inadequate tensegrity structure between the cells and matrix. Preconditioning, genetic modification and optimization of MSC culture conditions are key strategies to improve MSC functions in vitro and in vivo, and all of these procedures will contribute to improving MSC transplantation efficacy in tissue engineering and regenerative medicine. Preconditioning with various physical, chemical and biological factors is possible to preserve the stemness of MSCs for further application in studies and clinical tests. In this review, we mainly focus on preconditioning and the corresponding mechanisms for improving MSC activities in vitro and in vivo; we provide a glimpse into the promotion of MSC‐based cell therapy development for regenerative medicine. As a promising consequence, MSC transplantation can be applied for the treatment of some terminal diseases and can prolong the survival time of patients in the near future.

Alterations in the gut microbiome have been reported in liver cirrhosis, and probiotic interventions are considered a potential treatment strategy. This study aimed to evaluate the effects and mechanisms of Lactobacillus salivarius LI01, Pediococcus pentosaceus LI05, Lactobacillus rhamnosus GG, Clostridium butyricum MIYAIRI and Bacillus licheniformis Zhengchangsheng on CCl4-induced cirrhotic rats. Only administration of LI01 or LI05 prevented liver fibrosis and down-regulated the hepatic expression of profibrogenic genes. Serum endotoxins, bacterial translocations (BTs), and destruction of intestinal mucosal ultrastructure were reduced in rats treated with LI01 or LI05, indicating maintenance of the gut barrier as a mechanism; this was further confirmed by the reduction of not only hepatic inflammatory cytokines, such as TNF-α, IL-6, and IL-17A, but also hepatic TLR2, TLR4, TLR5 and TLR9. Metagenomic sequencing of 16S rRNA gene showed an increase in potential beneficial bacteria, such as Elusimicrobium and Prevotella, and a decrease in pathogenic bacteria, such as Escherichia. These alterations in gut microbiome were correlated with profibrogenic genes, gut barrier markers and inflammatory cytokines. In conclusion, L. salivarius LI01 and P. pentosaceus LI05 attenuated liver fibrosis by protecting the intestinal barrier and promoting microbiome health. These results suggest novel strategies for the prevention of liver cirrhosis.

Vaccination is a safe and effective approach to prevent deadly diseases. To increase vaccine production, we propose that a mechanical stimulation can enhance protein production. In order to prove this hypothesis, Sf9 insect cells were used to evaluate the increase in the expression of a fusion protein from hepatitis B virus (HBV S1/S2). We discovered that the ultrasound stimulation at a frequency of 1.5 MHz, intensity of 60 mW/cm2, for a duration of 10 minutes per day increased HBV S1/S2 by 27%. We further derived a model for transport through a cell membrane under the effect of ultrasound waves, tested the key assumptions of the model through a molecular dynamics simulation package, NAMD (Nanoscale Molecular Dynamics program) and utilized CHARMM force field in a steered molecular dynamics environment. The results show that ultrasound waves can increase cell permeability, which, in turn, can enhance nutrient / waste exchange thus leading to enhanced vaccine production. This finding is very meaningful in either shortening vaccine production time, or increasing the yield of proteins for use as vaccines.

Current research has demonstrated that mitochondrial morphology, distribution, and function are maintained by the balanced regulation of mitochondrial fission and fusion, and perturbation of the homeostasis between these processes has been related to cell or organ dysfunction and abnormal mitochondrial redistribution. Abnormal mitochondrial fusion induces the fragmentation of mitochondria from a tubular morphology into pieces; in contrast, perturbed mitochondrial fission results in the fusion of adjacent mitochondria. A member of the dynamin family of large GTPases, dynamin-related protein 1 (Drp1), effectively influences cell survival and apoptosis by mediating the mitochondrial fission process in mammals. Drp1-dependent mitochondrial fission is an intricate process regulating both cellular and organ dynamics, including development, apoptosis, acute organ injury, and various diseases. Only after clarification of the regulative mechanisms of this critical protein in vivo and in vitro will it set a milestone for preventing mitochondrial fission related pathological processes and refractory diseases.

Terminal liver disease is a major cause of death globally. The only ultimate therapeutic approach is orthotopic liver transplant. Because of the innate defects of organ transplantation, stem cell-based therapy has emerged as an effective alternative, based on the capacity of stem cells for multilineage differentiation and their homing to injured sites. However, the disease etiology, cell type, timing of cellular graft, therapeutic dose, delivery route, and choice of endpoints have varied between studies, leading to different, even divergent, results. In-vivo cell imaging could therefore help us better understand the fate and behaviors of stem cells to optimize cell-based therapy for liver regeneration. The primary imaging techniques in preclinical or clinical studies have consisted of optical imaging, magnetic resonance imaging, radionuclide imaging, reporter gene imaging, and Y chromosome-based fluorescence in-situ hybridization imaging. More attention has been focused on developing new or modified imaging methods for longitudinal and high-efficiency tracing. Herein, we provide a descriptive overview of imaging modalities and discuss recent advances in the field of molecular imaging of intrahepatic stem cell grafts.