查看更多>>摘要：Mesenchymal stem/stromal cells(MSCs)are widely distributed in the body and play essential roles in tissue regeneration and homeostasis.MSCs can be isolated from discarded tissues,expanded in vitro and used as therapeutics for autoimmune diseases and other chronic disorders.MSCs promote tissue regeneration and homeostasis by primarily acting on immune cells.At least six different types of MSCs have been isolated from postnatal dental tissues and have remarkable immunomodulatory properties.Dental stem cells(DSCs)have been demonstrated to have therapeutic effects on several systemic inflammatory diseases.Conversely,MSCs derived from nondental tissues such as the umbilical cord exhibit great benefits in the management of periodontitis in preclinical studies.Here,we discuss the main therapeutic uses of MSCs/DSCs,their mechanisms,extrinsic inflammatory cues and the intrinsic metabolic circuitries that govern the immunomodulatory functions of MSCs/DSCs.Increased understanding of the mechanisms underpinning the immunomodulatory functions of MSCs/DSCs is expected to aid in the development of more potent and precise MSC/DSC-based therapeutics.
查看更多>>摘要：Mesenchymal stromal cells(MSCs)have been extensively tested for the treatment of numerous clinical conditions and have demonstrated good safety but mixed efficacy.Although this outcome can be attributed in part to the heterogeneity of cell preparations,the lack of mechanistic understanding and tools to establish cell pharmacokinetics and pharmacodynamics,as well as the poorly defined criteria for patient stratification,have hampered the design of informative clinical trials.We and others have demonstrated that MSCs can rapidly undergo apoptosis after their infusion.Apoptotic MSCs are phagocytosed by monocytes/macrophages that are then reprogrammed to become anti-inflammatory cells.MSC apoptosis occurs when the cells are injected into patients who harbor activated cytotoxic T or NK cells.Therefore,the activation state of cytotoxic T or NK cells can be used as a biomarker to predict clinical responses to MSC treatment.Building on a large body of preexisting data,an alternative view on the mechanism of MSCs is that an inflammation-dependent MSC secretome is largely responsible for their immunomodulatory activity.We will discuss how these different mechanisms can coexist and are instructed by two different types of MSC"licensing":one that is cell-contact dependent and the second that is mediated by inflammatory cytokines.The varied and complex mechanisms by which MSCs can orchestrate inflammatory responses and how this function is specifically driven by inflammation support a physiological role for tissue stroma in tissue homeostasis,and it acts as a sensor of damage and initiator of tissue repair by reprogramming the inflammatory environment.
查看更多>>摘要：Hepatic fibrosis/cirrhosis is a significant health burden worldwide,resulting in liver failure or hepatocellular carcinoma(HCC)and accounting for many deaths each year.The pathogenesis of hepatic fibrosis/cirrhosis is very complex,which makes treatment challenging.Endogenous mesenchymal stromal cells(MSCs)have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis.Paradoxically,exogenous MSCs have also been used in clinical trials for liver cirrhosis,and their effectiveness has been observed in most completed clinical trials.There are still many issues to be resolved to promote the use of MSCs in the clinic in the future.In this review,we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis.We also investigated the clinical trials involving MSCs in liver cirrhosis,summarized the parameters that need to be standardized,and discussed how to promote the use of MSCs from a clinical perspective.
Annu DeviIsha PahujaShashi Prakash SinghAkanksha Verma...
600-612页
查看更多>>摘要：Mesenchymal stem cells(MSCs)play diverse roles ranging from regeneration and wound healing to immune signaling.Recent investigations have indicated the crucial role of these multipotent stem cells in regulating various aspects of the immune system.MSCs express unique signaling molecules and secrete various soluble factors that play critical roles in modulating and shaping immune responses,and in some other cases,MSCs can also exert direct antimicrobial effects,thereby helping with the eradication of invading organisms.Recently,it has been demonstrated that MSCs are recruited at the periphery of the granuloma containing Mycobacterium tuberculosis and exert"Janus"-like functions by harboring pathogens and mediating host protective immune responses.This leads to the establishment of a dynamic balance between the host and the pathogen.MSCs function through various immunomodulatory factors such as nitric oxide(NO),IDO,and immunosuppressive cytokines.Recently,our group has shown that M.tb uses MSCs as a niche to evade host protective immune surveillance mechanisms and establish dormancy.MSCs also express a large number of ABC efflux pumps;therefore,dormant M.tb residing in MSCs are exposed to a suboptimal dose of drugs.Therefore,it is highly likely that drug resistance is coupled with dormancy and originates within MSCs.In this review,we discussed various immunomodulatory properties of MSCs,their interactions with important immune cells,and soluble factors.We also discussed the possible roles of MSCs in the outcome of multiple infections and in shaping the immune system,which may provide insight into therapeutic approaches using these cells in different infection models.
Nadir KadriSylvie AmuEllen IacobaeusErik Boberg...
613-625页
查看更多>>摘要：Graft versus host disease(GvHD)is the clinical condition in which bone marrow-derived mesenchymal stromal cells(MSCs)have been most frequently studied.In this review,we summarize the experience from clinical trials that have paved the way to translation.While MSC-based therapy has shown an exceptional safety profile,identifying potency assays and disease biomarkers that reliably predict the capacity of a specific MSC batch to alleviate GvHD has been difficult.As GvHD diagnosis and staging are based solely on clinical criteria,individual patients recruited in the same clinical trial may have vastly different underlying biology,obscuring trial outcomes and making it difficult to determine the benefit of MSCs in subgroups of patients.An accumulating body of evidence indicates the importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness.A mode of action where intravascular MSC destruction is followed by monocyte-efferocytosis-mediated skewing of the immune repertoire in a permissive inflammatory environment would both explain why cell engraftment is irrelevant for MSC efficacy and stress the importance of biologic differences between responding and nonresponding patients.We recommend a combined analysis of clinical outcomes and both biomarkers of disease activity and MSC potency assays to identify patients with GvHD who are likely to benefit from MSC therapy.
查看更多>>摘要：Osteoarthritis(OA)is a degenerative multifactorial disease with concomitant structural,inflammatory,and metabolic changes that fluctuate in a temporal and patient-specific manner.This complexity has contributed to refractory responses to various treatments.MSCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression.Here,we evaluated 15 randomized controlled clinical trials(RCTs)and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA,and we found net positive effects of MSCs on mitigating pain and symptoms(improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints)and on cartilage protection and/or repair(18/21 clinical studies).We examined MSC dose,tissue of origin,and autologous vs.allogeneic origins as well as patient clinical phenotype,endotype,age,sex and level of OA severity as key parameters in parsing MSC clinical effectiveness.The relatively small sample size of 610 patients limited the drawing of definitive conclusions.Nonetheless,we noted trends toward moderate to higher doses of MSCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation.Evidence from preclinical studies is supportive of MSC anti-inflammatory and immunomodulatory effects,but additional investigations on immunomodulatory,chondroprotective and other clinical mechanisms of action are needed.We hypothesize that MSC basal immunomodulatory"fitness"correlates with OA treatment efficacy,but this hypothesis needs to be validated in future studies.We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory"fit"or engineered-to-be-fit-for-OA MSCs in well-designed,data-intensive clinical trials to advance the field.
查看更多>>摘要：Defective interleukin-6(IL-6)signaling has been associated with Th2 bias and elevated IgE levels.However,the underlying mechanism by which IL-6 prevents the development of Th2-driven diseases remains unknown.Using a model of house dust mite(HDM)-induced Th2 cell differentiation and allergic airway inflammation,we showed that IL-6 signaling in allergen-specific T cells was required to prevent Th2 cell differentiation and the subsequent IgE response and allergic inflammation.Th2 cell lineage commitment required strong sustained IL-2 signaling.We found that IL-6 turned off IL-2 signaling during early T-cell activation and thus inhibited Th2 priming.Mechanistically,IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of Suppressor Of Cytokine Signaling 3(SOCS3).This mechanism could be mimicked by pharmacological Janus Kinase-1(JAK1)inhibition.Collectively,our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.
查看更多>>摘要：The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis(MS).Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity.To date,however,the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood.Here,we report that stearoyl-CoA desaturase-1(SCD1),an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors,acts as an endogenous brake on regulatory T-cell(Treg)differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner.Guided by RNA sequencing and lipidomics analysis,we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase(ATGL).ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma.Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity,with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.
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