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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.

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.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by several symptoms of higher sensitivity of the lower urinary tract, such as bladder pain/discomfort, urgency, urinary frequency, pelvic pain and nocturia. Although the pathophysiology of IC/BPS is not fully understood, the hypothesis suggests that mast cell activation, glycosaminoglycan (GAG) layer defects, urothelium permeability disruption, inflammation, autoimmune disorder and infection are potential mechanisms. Mesenchymal stem cells (MSCs) have been proven to protect against tissue injury in IC/BPS by migrating into bladders, differentiating into key bladder cells, inhibiting mast cell accumulation and cellular apoptosis, inhibiting inflammation and oxidative stress, alleviating collagen fibre accumulation and enhancing tissue regeneration in bladder tissues. In addition, MSCs can protect against tissue injury in IC/BPS by secreting various soluble factors, including exosomes and other soluble factors, with antiapoptotic, anti-inflammatory, angiogenic and immunomodulatory properties in a cell-to-cell independent manner. In this review, we comprehensively summarized the current potential pathophysiological mechanisms and standard treatments of IC/BPS, and we discussed the potential mechanisms and therapeutic effects of MSCs and MSC-derived exosomes in alleviating tissue injury in IC/BPS models.

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.

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.

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.

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.

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.

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.

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.

Induced pluripotent stem cells (iPSCs) paved the way for research fields including cell therapy, drug screening, disease modeling and the mechanism of embryonic development. Although iPSC technology has been improved by various delivery systems, direct transduction and small molecule regulation, low reprogramming efficiency and genomic modification steps still inhibit its clinical use. Improvements in current vectors and the exploration of novel vectors are required to balance efficiency and genomic modification for reprogramming. Herein, we set out a comprehensive analysis of current reprogramming systems for the generation of iPSCs from somatic cells. By clarifying advantages and disadvantages of the current reprogramming systems, we are striding toward an effective route to generate clinical grade iPSCs.

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.

The elucidation of the underlying molecular mechanism of H2O2-induced adipocyte differentiation in mesenchymal stem cells (MSCs) is important for the development of treatments for metabolic diseases. The aim of the present study was to identify microRNA (miR)-330-5p, which targets retinoid X receptor γ (RXRγ) and to determine the function of H2O2-induced adipogenic differentiation of MSCs. During differentiation of MSCs into adipocytes induced by H2O2, miR-330-5p expression was decreased with a concomitant increase in RXRγ expression. A luciferase assay with RXRγ 3′-untranslated region (UTR) reporter plasmid, including the miR-330-5p-binding sequences, identified that the introduction of miR-330-5p decreases luciferase activity. However, it did not affect the activity of mutated RXRγ 3′-UTR reporter. Enforced expression of miR-330-5p significantly inhibited adipocyte differentiation by decreasing RXRγ mRNA and protein levels. In contrast, inhibition of the endogenous miR-330-5p promoted the formation of lipid droplets by rescuing RXRγ expression. Furthermore, the effects of inhibition of RXRγ were similar to those of overexpression of miR-330-5p on H2O2-induced adipogenic differentiation from MSCs. miR-330-5p inhibits H2O2-induced adipogenic differentiation of MSCs, and this is dependent on RXRγ. Taken together, the results of the present study revealed that miR-330-5p acts as a critical regulator of RXRγ, and is able to determinate the fate of MSCs to differentiate into adipocytes. This suggests that miR-330-5p and RXRγ may be target molecules for controlling metabolic diseases.

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.

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.

Reprogramming shifts somatic cells toward a pluripotent state, resulting in cells that are capable of producing any tissue type, which provides a unique system for regenerative medicine. However, the poor efficiency of this process has prevented the use of induced pluripotent stem cells (iPSCs) in clinical application of stem cell biology. Importantly, more recent work has highlighted novel reprogramming factors and new strategies to enhance the reprogramming process. In this review, we focus on the transition of somatic cells to iPSCs, effective routes to improve the reprogramming efficacy, and the potential mechanism underlying this process.

Mesenchymal stem cells (MSCs) are multipotent; non-hematopoietic stem cells. Because of their immunoregulatory abilities; MSCs are widely used for different clinical applications. Compared with that of other immune cells; the investigation of how MSCs specifically regulate B-cells has been superficial and insufficient. In addition; the few experimental studies on this regulation are often contradictory. In this review; we summarize the various interactions between different types or states of MSCs and B-cells; address how different types of MSCs and B-cells affect this interaction and examine how other immune cells influence the regulation of B-cells by MSCs. Finally; we hypothesize why there are conflicting results on the interaction between MSCs and B-cells in the literature.

Acute liver failure (ALF) is a kind of complicated syndrome. Furthermore, adipose-derived mesenchymal stem cells (ADMSCs) can serve as a useful cell resource for autotransplantation due to their abundance and micro-invasive accessability. However, it is unknown how ALF will influence the characteristics of ADMSCs and whether ADMSCs from patients suffering from end-stage liver diseases are potential candidates for autotransplantation. This study was designed to compare various properties of ALF-derived ADMSCs with normal ADMSCs in pig models, with regard to their cellular morphology, cell proliferative ability, cell apoptosis, expression of surface antigens, mitochondrial and lysosomal activities, multilineage potency, and expression of liver-specific genes. Our results showed that ALF does not influence the stem cell characteristics and cell activities of ADMSCs. Intriguingly, the expression levels of several liver-specific genes in ALF-derived ADMSCs are higher than in normal ADMSCs. In conclusion, our findings indicate that the stem cell characteristics and cell activities of ADMSCs were not altered by ALF and these cells can serve as a new source for regenerative medicine.

Various liver diseases result in terminal hepatic failure, and liver transplantation, cell transplantation and artificial liver support systems are emerging as effective therapies for severe hepatic disease. However, all of these treatments are limited by organ or cell resources, so developing a sufficient number of functional hepatocytes for liver regeneration is a priority. Liver regeneration is a complex process regulated by growth factors (GFs), cytokines, transcription factors (TFs), hormones, oxidative stress products, metabolic networks, and microRNA. It is well-known that the function of isolated primary hepatocytes is hard to maintain; when cultured in vitro, these cells readily undergo dedifferentiation, causing them to lose hepatocyte function. For this reason, most studies focus on inducing stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), hepatic progenitor cells (HPCs), and mesenchymal stem cells (MSCs), to differentiate into hepatocyte-like cells (HLCs) in vitro. In this review, we mainly focus on the nature of the liver regeneration process and discuss how to maintain and enhance in vitro hepatic function of isolated primary hepatocytes or stem cell-derived HLCs for liver regeneration. In this way, hepatocytes or HLCs may be applied for clinical use for the treatment of terminal liver diseases and may prolong the survival time of patients in the near future.