In vitro augmentation of mesenchymal stem cells viability in stressful microenvironments: In vitro augmentation of mesenchymal stem cells viability

Mesenchymal stem cells (MSCs) are under intensive investigation for use in cell-based therapies because their differentiation abilities, immunomodulatory effects, and homing properties offer potential for significantly augmenting regenerative capacity of many tissues. Nevertheless, major impediments to their therapeutic application, such as low proliferation and survival rates remain as obstacles to broad clinical use of MSCs. Another major challenge to evolution of MSC-based therapies is functional degradation of these cells as a result of their exposure to oxidative stressors during isolation. Indeed, oxidative stress-mediated MSC depletion occurs due to inflammatory processes associated with chemotherapy, radiotherapy, and expression of pro-apoptotic factors, and the microenvironment of damaged tissue in patients receiving MSC therapy is typically therapeutic not favorable to their survival. For this reason, any strategies that enhance the viability and proliferative capacity of MSCs associated with their therapeutic use are of great value. Here, recent strategies used by various researchers to improve MSC allograft function are reviewed, with particular focus on in vitro conditioning of MSCs in preparation for clinical application. Preconditioning, genetic manipulation, and optimization of MSC culture conditions are some examples of the methodologies described in the present article, along with novel strategies such as treatment of MSCs with secretome and MSC-derived microvesicles. This topic material is likely to find value as a guide for both research and clinical use of MSC allografts and for improvement of the value that use of these cells brings to health care.     

Strategies to enhance immunomodulatory properties and reduce heterogeneity in mesenchymal stromal cells during ex vivo expansion

Therapies using mesenchymal stromal cells (MSCs) to treat immune and inflammatory conditions are now at an exciting stage of development, with many MSC-based products progressing to phase II and III clinical trials. However, a major bottleneck in the clinical translation of allogeneic MSC therapies is the variable immunomodulatory properties of MSC products due to differences in their tissue source, donor heterogeneity and processes involved in manufacturing and banking. This variable functionality of MSC products likely contributes to the substantial inconsistency observed in the clinical outcomes of phase III trials of MSC therapies; several trials have failed to reach the primary efficacy endpoint. In this review, we discuss various strategies to consistently maintain or enhance the immunomodulatory potency of MSCs during ex vivo expansion, which will enable the manufacture of allogeneic MSC banks that have high potency and low variability. Biophysical and biochemical priming strategies, the use of culture additives such as heparan sulfates, and genetic modification can substantially enhance the immunomodulatory properties of MSCs during in vitro expansion. Furthermore, robust donor screening, the use of biomarkers to select for potent MSC subpopulations, and rigorous quality testing to improve the release criteria for MSC banks have the potential to reduce batch-to-batch heterogeneity and enhance the clinical efficacy of the final MSC product. Machine learning approaches to develop predictive models of individual patient response can enable personalized therapies and potentially establish correlations between in vitro potency measurements and clinical outcomes in human trials.     

Immunomodulatory properties of dental tissue-derived mesenchymal stem cells: Implication in disease and tissue regeneration

Mesenchymal stem cells (MSCs) are considered as an attractive tool for tissue regeneration and possess a strong immunomodulatory ability. Dental tissue-derived MSCs can be isolated from different sources, such as the dental pulp, periodontal ligament, deciduous teeth, apical papilla, dental follicles and gingiva. According to numerous in vitro studies, the effect of dental MSCs on immune cells might depend on several factors, such as the experimental setting, MSC tissue source and type of immune cell preparation. Most studies have shown that the immunomodulatory activity of dental MSCs is strongly upregulated by activated immune cells. MSCs exert mostly immunosuppressive effects, leading to the dampening of immune cell activation. Thus, the reciprocal interaction between dental MSCs and immune cells represents an elegant mechanism that potentially contributes to tissue homeostasis and inflammatory disease progression. Although the immunomodulatory potential of dental MSCs has been extensively investigated in vitro, its role in vivo remains obscure. A few studies have reported that the MSCs isolated from inflamed dental tissues have a compromised immunomodulatory ability. Moreover, the expression of some immunomodulatory proteins is enhanced in periodontal disease and even shows some correlation with disease severity. MSC-based immunomodulation may play an essential role in the regeneration of different dental tissues. Therefore, immunomodulation-based strategies may be a very promising tool in regenerative dentistry.     

Modulation of the in vitro angiogenic potential of human mesenchymal stromal cells from different tissue sources

Mesenchymal stromal cells (MSCs) have been widely exploited for the treatment of several conditions due to their intrinsic regenerative and immunomodulatory properties. MSC have demonstrated to be particularly relevant for the treatment of ischemic diseases, where MSC-based therapies can stimulate angiogenesis and induce tissue regeneration. Regardless of the condition targeted, recent analyses of MSC-based clinical trials have demonstrated limited benefits indicating a need to improve the efficacy of this cell product. Preconditioning MSC ex vivo through microenvironment modulation was found to improve MSC survival rate and thus prolong their therapeutic effect. This workstudy aims at enhancing the in vitro angiogenic capacity of a potential MSC-based medicinal product by comparing different sources of MSC and culture conditions. MSC from three different sources (bone marrow [BM], adipose tissue [AT], and umbilical cord matrix [UCM]) were cultured with xenogeneic-/serum-free culture medium under static conditions and their angiogenic potential was studied. Results indicated a higher in vitro angiogenic capacity of UCM MSC, compared with cells derived from BM and AT. Physicochemical preconditioning of UCM MSC through a microcarrier-based culture platform and low oxygen concentration (2% O₂, compared with atmospheric air) increased the in vitro angiogenic potential of the cultured cells. Envisaging the clinical manufacturing of an allogeneic, off-the-shelf MSC-based product, preconditioned UCM MSC maintain the angiogenic gene expression profile upon cryopreservation and delivery processes in the conditions of our study. These results are expected to contribute to the development of MSC-based therapies in the context of angiogenesis.     

Pre-conditioning mesenchymal stromal cell spheroids for immunomodulatory paracrine factor secretion

Background aimsMesenchymal stromal cells (MSCs) exhibit the inherent potential to regulate multiple signaling pathways and cell types that contribute to the pathogenesis of inflammatory and immune diseases. However, more recent studies have suggested that the secretion of immunomodulatory factors by MSCs can be enhanced by three-dimensional aggregation or pro-inflammatory cytokine treatment.MethodsHuman MSC spheroids were formed by forced aggregation into agarose micro-wells and subsequently cultured in either minimal essential medium alpha supplemented with fetal bovine serum or serum-free, defined MesenCult-XF medium (STEMCELL Technologies, Vancouver, Canada). A subset of the spheroids were treated with pro-inflammatory cytokines interferon (IFN)-γ or tumor necrosis factor (TNF)-α or both for 4 days. Immunomodulatory factor (prostaglandin E₂, indoleamine 2,3-dioxygenase, transforming growth factor-β1 and interleukin-6) secretion was quantified after 4 days of culture, and the immunomodulatory activity of MSCs was assessed by quantifying activated macrophage expression of TNF-α after trans-well co-culture.ResultsCulturing human MSCs as three-dimensional aggregates increased secretion of immunomodulatory paracrine factors, which was enhanced further by treatment with IFN-γ and TNF-α, demonstrating that these parameters can synergistically enhance endogenous human MSC immunomodulatory properties. However, immunomodulatory factor secretion was found to be highly dependent on the composition of cell culture medium. Human MSCs cultured in MesenCult-XF medium displayed significantly less expression of prostaglandin E₂, indoleamine 2,3-dioxygenase, transforming growth factor-β1 and interleukin-6 compared with human MSCs cultured in medium supplemented with fetal bovine serum. Finally, pre-conditioning of human MSC spheroids with IFN-γ and TNF-α resulted in greater immunomodulatory activity in a macrophage co-culture assay.ConclusionsAltogether, engineering the environment of human MSCs to develop pre-conditioning strategies for enhancing human MSC immunomodulation may be a simple approach for improving MSC-based therapies for the treatment of inflammatory and immune diseases.     

The novel role of SERPINB9 in cytotoxic protection of human mesenchymal stem cells

Clinical trials using allogeneic mesenchymal stem cells (MSCs) are ongoing for the purpose of providing therapeutic benefit for a variety of human disorders. Pertinent to their clinical use are the accessibility to sufficient quantities of these cells allowing for repetitive administration, as well as a better understanding of the specific mechanisms by which allogeneic MSCs evade host immune responses that in turn influence their life span following administration. In this report, we sought to characterize and compare human peripheral blood MSCs (hPB-MSCs) with bone marrow-derived MSCs. hPB-MSCs met the established criteria to characterize this cellular lineage, including capacity for self-renewal, differentiation into tissues of mesodermal origin, and expression of phenotypic surface markers. In addition, hPB-MSCs suppressed alloreactive proliferation as well as the production of proinflammatory cytokines. Examination of the mechanisms by which allogeneic MSCs evade the host immune response, which is crucial for their therapeutic use, demonstrated that constitutive expression of serine protease inhibitor 9 (PI-9) on hPB-MSCs and bone marrow-derived MSCs is a major defense mechanism against granzyme B-mediated destruction by NK cells. Similarly, MSCs treated with small interfering RNA for PI-9 increased MSC cellular death, whereas expression of transgenic PI-9 following retroviral transduction protected MSCs. These data significantly advance our understanding of the immunomodulatory role for hPB-MSCs as well as the mechanisms by which they evade host immune responses. These findings contribute to the development of MSC-based therapies for diseases.     

A20 plays a critical role in the immunoregulatory function of mesenchymal stem cells

Mesenchymal stem cells (MSCs) possess an immunoregulatory capacity and are a therapeutic target for many inflammation‐related diseases. However, the detailed mechanisms of MSC‐mediated immunosuppression remain unclear. In this study, we provide new information to partly explain the molecular mechanisms of immunoregulation by MSCs. Specifically, we found that A20 expression was induced in MSCs by inflammatory cytokines. Knockdown of A20 in MSCs resulted in increased proliferation and reduced adipogenesis, and partly reversed the suppressive effect of MSCs on T cell proliferation in vitro and inhibited tumour growth in vivo. Mechanistic studies indicated that knockdown of A20 in MSCs inhibited activation of the p38 mitogen‐activated protein kinase (MAPK) pathway, which potently promoted the production of tumour necrosis factor (TNF)‐α and inhibited the production of interleukin (IL)‐10. Collectively, these data reveal a crucial role of A20 in regulating the immunomodulatory activities of MSCs by controlling the expression of TNF‐α and IL‐10 in an inflammatory environment. These findings provide novel insights into the pathogenesis of various inflammatory‐associated diseases, and are a new reference for the future development of treatments for such afflictions.     

Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: Role of secretome and exosomes

Over the last decades, mesenchymal stem cells (MSCs) have been extensively studied with regard to their potential applications in regenerative medicine. In rheumatic diseases, MSC-based therapy is the subject of great expectations for patients who are refractory to proposed treatments such as rheumatoid arthritis (RA), or display degenerative injuries without possible curative treatment, such as osteoarthritis (OA). The therapeutic potential of MSCs has been demonstrated in several pre-clinical models of OA or RA and both the safety and efficacy of MSC-based therapy is being evaluated in humans. The predominant mechanism by which MSCs participate to tissue repair is through a paracrine activity. Via the production of a multitude of trophic factors with various properties, MSCs can reduce tissue injury, protect tissue from further degradation and/or enhance tissue repair. However, a thorough in vivo examination of MSC-derived secretome and strategies to modulate it are still lacking. The present review discusses the current understanding of the MSC secretome as a therapeutic for treatment of inflammatory or degenerative pathologies focusing on rheumatic diseases. We provide insights on and perspectives for future development of the MSC secretome with respect to the release of extracellular vesicles that would have certain advantages over injection of living MSCs or administration of a single therapeutic factor or a combination of factors.     

Mesenchymal stromal cells; a new horizon in regenerative medicine

In recent decades, mesenchymal stromal cells (MSCs) biomedical utilizing has attracted worldwide growing attention. After the first report of the human MSCs obtaining from the bone marrow (BM) tissue, these cells were isolated from wide types of the other tissues, ranging from adipose tissue to dental pulp. Their specific characteristics, comprising self-renewality, multipotency, and availability accompanied by their immunomodulatory properties and little ethical concern denote their importance in the context of regenerative medicine. Considering preclinical studies, MSCs can modify immune reactions during tissue repair and restoration, providing suitable milieu for tissue recovery; on the other hand, they can be differentiated into comprehensive types of the body cells, such as osteoblast, chondrocyte, hepatocyte, cardiomyocyte, fibroblast, and neural cells. Though a large number of studies have investigated MSCs capacities in regenerative medicine in varied animal models, the oncogenic capability of unregulated MSCs differentiation must be more assessed to enable their application in the clinic. In the current review, we provide a brief overview of MSCs sources, isolation, and expansion as well as immunomodulatory activities. More important, we try to collect and discuss recent preclinical and clinical research and evaluate current challenges in the context of the MSC-based cell therapy for regenerative medicine.     

Role of aryl hydrocarbon receptor in mesenchymal stromal cell activation:A minireview

Mesenchymal stromal cells(MSCs) possess great therapeutic advantages due to their ability to produce a diverse array of trophic/growth factors related to cytoprotection and immunoregulation.MSC activation via specific receptors is a crucial event for these cells to exert their immunosuppressive response.The aryl-hydrocarbon receptor(Ah R) is a sensitive molecule for external signals and it is expressed in MSCs and,upon positive activation,may potentially regulate the MSC-associated immunomodulatory function.Consequently,signalling pathways linked to Ah R activation can elucidate some of the molecular cascades involved in MSC-mediated immunosuppression.In this minireview,we have noted some important findings concerning MSC regulation via Ah R,highlighting that its activation is associated with improvement in migration and immunoregulation,as well as an increase in pro-regenerative potential.Thus,Ah R-mediated MSC activation can contribute to new perspectives on MSC-based therapies,particularly those directed at immune-associated disorders.     

Implanted bone marrow-derived mesenchymal stem cells fail to metabolically stabilize or recover electromechanical function in infarcted hearts

Mesenchymal stem cells (MSCs) have been used with success in several clinical applications for clinical treatment of ischemic hearts. However, the reported effects of MSC-based therapy on myocardial infarction (MI) are inconsistent. In particular, the preventive effects of MSC-based therapy on arrhythmic sudden death and metabolic disorders after infarction remain controversial. Here, we investigated the effects of MSCs on reverse remodeling in an infarcted myocardium, and found that MSC-therapy failed to achieve the complete regeneration of infarcted myocardium. Histological analyses showed that although infarct size and interstitial fibrosis induced by MI recovered significantly after MSC treatment, these improvements were marginal, indicating that a significant amount of damaged tissue was still present. Furthermore, transplanted MSCs had slight anti-apoptotic and anti-inflammatory effects in MSC-implanted regions and no significant improvements in cardiac function were observed, suggesting that naïve MSCs might not be the right cell type to treat myocardial infarction. Furthermore, small ion profiling using ToF-SIMS revealed that the metabolic stabilization provided by the MSCs implantation was not significant compared to the sham group. Together, these results indicate that pretreatment of MSCs is needed to enhance the benefits of MSCs, particularly when MSCs are used to treat arrhythmogenicity and metabolically stabilize infarcted myocardium.     

Rheumatoid arthritis: From synovium biology to cell-based therapy

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects the synovial joints and, if not treated properly, can lead to multiple progressive articular and extra-articular damage. Its pathogenesis is primarily associated with an inadequate immune response and dysregulated cytokine production. However, RA is also linked to disruption in oxygen metabolism, impaired redox signaling, acidosis and aberrant intercellular communication. Even though treatment modalities have made RA a manageable disease, a significant number of patients still do not respond satisfactorily or suffer considerably from the adverse events of conventional therapy. In recent years, cell-based strategies, especially the administration of the mesenchymal/medicinal stem/signaling cells (MSCs), have been proposed as a novel and very promising therapeutic approach. RA patients may benefit from the potent anti-inflammatory and immunomodulatory properties and tissue-repair potential of MSCs. Furthermore, the satisfactory safety profile of MSC therapy has been already demonstrated in several clinical studies. This review summarizes current understanding of the pathomechanism behind RA at the molecular and cellular level and focuses on MSC-based clinical research and applications of MSCs for RA treatment.     

CCR7 Expressing Mesenchymal Stem Cells Potently Inhibit Graft-versus-Host Disease by Spoiling the Fourth Supplemental Billingham’s Tenet

The clinical acute graft-versus-host disease (GvHD)-therapy of mesenchymal stem cells (MSCs) is not as satisfactory as expected. Secondary lymphoid organs (SLOs) are the major niches serve to initiate immune responses or induce tolerance. Our previous study showed that CCR7 guide murine MSC line C3H10T1/2 migrating to SLOs. In this study, CCR7 gene was engineered into murine MSCs by lentivirus transfection system (MSCs/CCR7). The immunomodulatory mechanism of MSCs/CCR7 was further investigated. Provoked by inflammatory cytokines, MSCs/CCR7 increased the secretion of nitric oxide and calmed down the T cell immune response in vitro. Immunofluorescent staining results showed that transfused MSCs/CCR7 can migrate to and relocate at the appropriate T cell-rich zones within SLOs in vivo. MSCs/CCR7 displayed enhanced effect in prolonging the survival and alleviating the clinical scores of the GvHD mice than normal MSCs. Owing to the critical relocation sites, MSCs/CCR7 co-infusion potently made the T cells in SLOs more naïve like, thus control T cells trafficking from SLOs to the target organs. Through spoiling the fourth supplemental Billingham’s tenet, MSCs/CCR7 potently inhibited the development of GvHD. The study here provides a novel therapeutic strategy of MSCs/CCR7 infusion at a low dosage to give potent immunomodulatory effect for clinical immune disease therapy.     

Mesenchymal stem cells and immunomodulation: current status and future prospects

The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy.     

Activated T cells modulate immunosuppression by embryonic-and bone marrow-derived mesenchymal stromal cells through a feedback mechanism

Background aimsHuman embryonic stem cell (hESC)-derived mesenchymal stromal cells (MSC) (hESC-MSC) are an alternative source of MSC to bone marrow (BM)-derived MSC (BM-MSC), which are being investigated in clinical trials for their immunomodulatory potential. hESC-MSC have the advantage of being consistent because each batch can be generated from hESC under defined conditions. In contrast, BM-MSC have a limited proliferative capacity.MethodsThe ability to suppress the proliferation of anti-CD3/CD28-stimulated CD4 ⁺ T cells by hESC-MSC was compared with adult BM-MSC and neonatal foreskin fibroblast (Fb).ResultshESC-MSC suppress the proliferation of CD4 ⁺ T cells in both contact and transwell systems, although inhibition is less in the transwell system. hESC-MSC are approximately 2-fold less potent (67 cells/100 T cells) than BM-MSC and Fb (37 and 34 cells/100 T cells, respectively) at suppressing T-cell proliferation by 50% in a transwell [inhibitory concentration(IC)₅₀]. The anti-proliferative effect is not contact-dependent but requires the presence of factors such as interferon (IFN)-γ produced by activated T cells. IFN-γ induces the expression of indoleamine-2,3-dioxygenase (IDO) in hESC-MSC, BM-MSC and Fb, contributing to their immunosuppressive property.ConclusionsThe feedback loop between MSC or Fb and activated T cells may limit the immunosuppressive effects of MSC and Fb to sites containing ongoing immunologic or inflammatory responses where activated T cells induce the up-regulation of IDO and immunomodulatory properties of MSC and Fb. These data demonstrate that hESC-MSC may be evaluated further as an allogeneic cell source for therapeutic applications requiring immunosuppression.     

Neuroprotective Potential of Mesenchymal Stem Cell-Based Therapy in Acute Stages of TNBS-Induced Colitis in Guinea-Pigs

Background & Aims

The therapeutic benefits of mesenchymal stem cells (MSCs), such as homing ability, multipotent differentiation capacity and secretion of soluble bioactive factors which exert neuroprotective, anti-inflammatory and immunomodulatory properties, have been attributed to attenuation of autoimmune, inflammatory and neurodegenerative disorders. In this study, we aimed to determine the earliest time point at which locally administered MSC-based therapies avert enteric neuronal loss and damage associated with intestinal inflammation in the guinea-pig model of colitis.

Methods

At 3 hours after induction of colitis by 2,4,6-trinitrobenzene-sulfonate (TNBS), guinea-pigs received either human bone marrow-derived MSCs, conditioned medium (CM), or unconditioned medium by enema into the colon. Colon tissues were collected 6, 24 and 72 hours after administration of TNBS. Effects on body weight, gross morphological damage, immune cell infiltration and myenteric neurons were evaluated. RT-PCR, flow cytometry and antibody array kit were used to identify neurotrophic and neuroprotective factors released by MSCs.

Results

MSC and CM treatments prevented body weight loss, reduced infiltration of leukocytes into the colon wall and the myenteric plexus, facilitated repair of damaged tissue and nerve fibers, averted myenteric neuronal loss, as well as changes in neuronal subpopulations. The neuroprotective effects of MSC and CM treatments were observed as early as 24 hours after induction of inflammation even though the inflammatory reaction at the level of the myenteric ganglia had not completely subsided. Substantial number of neurotrophic and neuroprotective factors released by MSCs was identified in their secretome.

Conclusion

MSC-based therapies applied at the acute stages of TNBS-induced colitis start exerting their neuroprotective effects towards enteric neurons by 24 hours post treatment. The neuroprotective efficacy of MSC-based therapies can be exerted independently to their anti-inflammatory effects.     

A chemically defined biomimetic surface for enhanced isolation efficiency of high-quality human mesenchymal stromal cells under xenogeneic/serum-free conditions

Background aimsMesenchymal stromal cells (MSCs) are one of the most frequently used cell types in regenerative medicine and cell therapy. Generating sufficient cell numbers for MSC-based therapies is constrained by (i) their low abundance in tissues of origin, which imposes the need for significant ex vivo cell expansion; (ii) donor-specific characteristics, including MSC frequency/quality, that decline with disease state and increasing age; and (iii) cellular senescence, which is promoted by extensive cell expansion and results in decreased therapeutic functionality. The final yield of a manufacturing process is therefore primarily determined by the applied isolation procedure and its efficiency in isolating therapeutically active cells from donor tissue. To date, MSCs are predominantly isolated using media supplemented with either serum or its derivatives, which poses safety and consistency issues.MethodsTo overcome these limitations while enabling robust MSC production with constant high yield and quality, the authors developed a chemically defined biomimetic surface coating called isoMATRIX (denovoMATRIX GmbH, Dresden, Germany) and tested its performance during isolation of MSCs.ResultsThe isoMATRIX facilitates the isolation of significantly higher numbers of MSCs in xenogeneic (xeno)/serum-free and chemically defined conditions. The isolated cells display a smaller cell size and higher proliferation rate than those derived from a serum-containing isolation procedure and a strong immunomodulatory capacity. The high proliferation rates can be maintained up to 5 passages after isolation and cells even benefit from a switch towards a proliferation-specific MSC matrix (myMATRIX MSC) (denovoMATRIX GmbH, Dresden, Germany).ConclusionIn sum, isoMATRIX promotes enhanced xeno/serum-free and chemically defined isolation of human MSCs and supports consistent and reliable cell performance for improved stem cell-based therapies.     

Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells

In recent years, a large number of studies have contributed to our understanding of the immunomodulatory mechanisms used by multipotent mesenchymal stem cells (MSCs). Initially isolated from the bone marrow (BM), MSCs have been found in many tissues but the strong immunomodulatory properties are best studied in BM MSCs. The immunomodulatory effects of BM MSCs are wide, extending to T lymphocytes and dendritic cells, and are therapeutically useful for treatment of immune-related diseases including graft-versus-host disease as well as possibly autoimmune diseases. However, BM MSCs are very rare cells and require an invasive procedure for procurement. Recently, MSCs have also been found in fetal-stage embryo-proper and extra-embryonic tissues, and these human fetal MSCs (F-MSCs) have a higher proliferative profile, and are capable of multilineage differentiation as well as exert strong immunomodulatory effects. As such, these F-MSCs can be viewed as alternative sources of MSCs. We review here the current understanding of the mechanisms behind the immunomodulatory properties of BM MSCs and F-MSCs. An increase in our understanding of MSC suppressor mechanisms will offer insights for prevalent clinical use of these versatile adult stem cells in the near future.     

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

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.