1、Stem cells are undifferentiated cells of metazoans that are characterized by their ability to both self-renew through symmetrical division and differentiate into specialized cell types through asymmetrical division.Stem cells can be classified according to their differentiation potential:pluripotent
2、 stem cells,such as embryonic stem cells,can presumably give rise to any cell type,whereas multi-potent stem cells have limited differentiation potential and unipotent stem cells can differentiate only along one lineage.In tissues,stem cells function to maintain homeostasis.They are often quiescent
3、and retain their progenitor properties by self-renewing.Activation(for example,by extrinsic cellular factors or damaged resident cells)induces stem cells to proliferate and differentiate to regenerate the damaged tissue.In addition to regenerat-ing tissue in response to normal wear and tear,trauma o
4、r disease,resident stem cells are now also understood to actively communicate with the tissue microenvironment,especially with inflammatory components.Mesenchymal stem cells(MSCs)are among the most widely studied multipotent stem cells.Unlike many other stem cells that are tissue-specific,MSCs have
5、been identified in various tissues.Their stemness is exemplified by their ability to differentiate into osteo-blasts,chondrocytes and adipocytes1.However,MSCs are also often referred to as mesenchymal stromal cells owing to their ability to sustain the homeostasis of the tissue microenvironment by s
6、upporting the functions of parenchymal cells,such as haematopoietic stem cells(HSCs)2,3.Due to variations in experimental protocols and cell sources between studies,no consensus exists regarding the nomenclature of these cells.In this Review,we use MSCs to refer to the stem and stromal functions of
7、these cells.Owing to the lack of specific markers to study endogenous MSCs,most of our knowledge of the biological properties of MSCs has been obtained from the study of invitro expanded and exogenously administered MSCs.Exogenously administered MSCs have been found to accumulate at damaged tissues4
8、,where they promote tissue regeneration through cell replacement or by empowering the regenerative Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseasesYufangShi1,2*,YuWang2,QingLi2,KeliLiu2,JianquanHou1,ChangshunShao1 and YingWang2*Abstract|Mesenchymal stem cell
9、s(MSCs;also referred to as mesenchymal stromal cells)have attracted much attention for their ability to regulate inflammatory processes.Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohns disease,graft-versus-host disease,diab
10、etic nephropathy and organ fibrosis.The mechanisms by which MSCs exert their therapeutic effects are multifaceted,but in general,these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation.Studies over t
11、he past few years have demonstrated that when exposed to an inflammatory environment,MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators,including immunosuppressive molecules,growth factors,exosomes,chemokines,complement components an
12、d various metabolites.Interestingly,even nonviable MSCs can exert beneficial effects,with apoptotic MSCs showing immunosuppressive functions invivo.Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines,the net outcomes of MSC activat
13、ion might vary depending on the levels and the types of inflammation within the residing tissues.Here,we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.1The First Affiliated Hospital of Soochow University,State Key Lab
14、oratory of Radiation Medicine and Protection,Institutes for Translational Medicine,Soochow University,Suzhou,China.2CAS Key Laboratory of Tissue Microenvironment and Tumor,Shanghai Institute of Nutrition and Health,Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of M
15、edicine,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai,China.*e-mail:;https:/doi.org/10.1038/s41581-018-0023-5 2018 Macmillan Publishers Limited,part of Springer Nature.All rights reserved.NATuRe RevIewS|NephRologyReviews volume 14|AuGuST 2018|493capacity of insitu ce
16、lls4.For instance,inflammatory signals stimulate MSCs to produce a variety of growth factors,which facilitate tissue repair by promoting angio genesis,remodelling of extracellular matrix(ECM)and differentiation of tissue progenitor cells.MSCs can also potently modulate immune cells in the inflamed t
17、issue microenvironment.Interestingly,the immunomodulatory capabilities of MSCs are not constitutive but rather are endowed and determined by the types and intensity of inflammation4.Indeed,find-ings from preclinical and clinical studies support the promising regenerative role of MSCs in pathological
18、 conditions characterized by inflammation,including graft-versus-host disease(GvHD),multiple sclerosis and diabetic nephropathy.Here,we summarize current understanding of the pathophysiological features and plasticity of MSCs as well as the mechanisms of MSC-mediated immunomod-ulation,with particula
19、r emphasis on the tissue micro-environment that critically shapes the properties of MSCs.We also examine preclinical and clinical applica-tions of MSCs and approaches to improve MSC-based strategies for patients with inflammatory diseases.Isolation and characterization of MSCsMSCs were first discove
20、red in the late 1960s in cultures of guinea pig bone marrow5.These spindle-shaped,plastic-adherent cells formed colonies and could spon-taneously differentiate into osteocytes and osteoblasts invivo.The multipotent nature of these cells was further confirmed by the observation that bone fragments co
21、uld continue forming bone and support haematopoiesis fol-lowing extramedullary transplantation,indicating the existence of a cell population that supports osteogenesis and haematopoiesis6.Subsequent investigations in the 1990s revealed that MSCs isolated from human bone marrow aspirates could differ
22、entiate into osteogenic,chondrogenic and adipogenic mesenchymal cell lineages invitro7.Definitive proof that MSCs are stem cells came from a study in which single-cell colonies derived from human bone were expanded and transplanted subcuta-neously into immunodeficient mice.These transplanted cells f
23、ormed bones and developed niches that supported murine haematopoiesis,demonstrating both stem cell and stromal properties of these cells8.These early studies identified MSCs on the basis of their ability to adhere to plastic and form colonies.Later studies identified CD146 a protein initially though
24、t to be a marker of osteoprogenitor cells as a marker of MSCs with multilineage potential9,10.A 2007 study showed CD146+osteoprogenitor cells most likely MSCs to be important for the organization of the haematopoietic compartment,in line with findings that exo genously administered MSCs can enhance
25、the engraftment of transplanted HSCs11.MSCs have also been studied in other transplantation models,such as mismatched skin grafting,in which intravenous administration of autologous or allogeneic MSCs pro-longed graft survival12,highlighting the ability of these cells to support resident cells.Beyon
26、d this supportive function,invitro studies have demonstrated MSCs to have immunoregulatory functions12,prompting intense study of the interactions between MSCs and immune cells(see below).Markers and sources of MSCsA fibroblast-like morphology(Box1)and expres-sion of specific cell-surface markers(th
27、at is,CD73+CD90+CD105+CD45CD34CD14CD79HLA-DR)are the minimal and well-accepted criteria for the iden-tification of MSCs.CD146 is also used to recognize perivascular human MSCs;however,the specific recog-nition of MSCs by CD146 expression is limited,as both CD146+and CD146 populations possess tri-lin
28、eage differentiation capacity.CD146+MSCs are more prone to differentiate into vascular smooth muscle cells than are CD146 cells10,13.Using these markers together with assessment of tri-lineage differentiation potential,MSCs have been identified and isolated from a variety of tis-sues,including bone
29、marrow,umbilical cord,placenta,adipose tissue,kidney,liver,lung and dental tissues14(Fig.1).Although limited data are available,preliminary observations suggest that MSCs derived from different sources differ in their immunomodulatory properties.For example,adipose-tissue-derived MSCs(AD-MSCs)expres
30、s higher levels of IL-6 and transforming growth factor-(TGF)than bone-marrow-derived MSCs(BM-MSCs).Such differences could relate to the higher metabolic activity of AD-MSCs as a consequence of cues from adipose tissue15.As another example,the neuroprotective response of dental-pulp-derived MSCs was
31、superior to that of BM-MSCs in a rat model of cerebral ischaemic injury16.However,why MSCs from different tissues differ in their tissue-protective and immunomodulatory properties is unclear.MSCs in different locations are influenced by differ-ent signalling inputs,as exemplified by the metabolic cu
32、es endowed by adipose tissue on AD-MSCs.Invivo studies using genetic tracing have revealed a high level of heterogeneity between MSCs even within the same organ,indicating that cell-intrinsic differences likely exist.Tracing experiments have now been performed using nestin3,leptin receptor(LEPR)17,c
33、hondroi-tin sulfate proteoglycan 4(also known as NG2)18 and paired-related homeobox protein 1(PRX1)19 to identify BM-MSCs and zinc-finger protein GLI1 to identify heart,lung,kidney and liver resident MSCs20.Of note,Key pointsmesenchymal stem cells(mSCs;also known as mesenchymal stromal cells)activel
34、y contribute to the microenvironment of injured tissues,where they promote tissue regenerationbycellreplacement,byempoweringtheregenerativecapacityofinsitucells and through immunomodulatory mechanisms.The plasticity of immunoregulation by mSCs is controlled by the intensity and complexity of inflamm
35、atory stimuli.multiple factors,including immunosuppressive factors,growth factors,exosomes,chemokines and apoptotic cells,contribute to the immunosuppressive mechanisms of mSCs.Given the plasticity of the immunoregulatory phenotype of mSCs,inflammatory status and concurrent use of immunosuppressants
36、 should be considered when administering mSCs for the treatment of inflammatory diseases.Greater understanding of the mechanisms that control the plasticity of mSC immunoregulation will lead to the development of novel therapeutic strategies.ColoniesCell communities in which all of the daughter cell
37、s are derived from one ancestor cell.2018 Macmillan Publishers Limited,part of Springer Nature.All rights 2018|volume 14 overlap exists between MSCs labelled with these dif-ferent markers,whereas different populations of MSCs can have different effects on tissue resident cells.For example,nestin+MSC
38、s in bone marrow express genes involved in HSC maintenance,and studies involving the depletion or transplantation of nestin+cells into lethally irradiated mice have demonstrated a role for these cells in haematopoiesis3.NG2+MSCs,which express high levels of nestin,are located near the endosteum and
39、maintain a niche for quiescent HSCs.By contrast,per-isinusoidal LEPR+MSCs possess low levels of nestin and are thought to be important for niches of activated HSCs18(Fig.1).Thus,MSCs exhibit location-specific characteristics,but further work is required to more definitely define the properties and f
40、unctions of these cells,particularly in human tissue.Determinants of immunological activitySeveral studies have demonstrated the ability of invitro expanded MSCs to facilitate the repair and regeneration of damaged tissue through their immunomodulatory actions.Interestingly,tissue resident MSCs may
41、not be as effective as infused MSCs in restoring immunological homeostasis in damaged tissues.One possible explana-tion for this difference is that invitro expanded MSCs are often infused in large quantities(12 106 cells per kilogram of body weight compared with a normal con-centration of 10 years a
42、go demonstrated that apoptotic splenic cells prolonged the engraftment of allogeneic heart trans-plants106,likely by promoting the expression of iNOS107 or IDO108,similar to the mechanisms of apoptotic MSCs.Apoptosis of MSCs administered to humans might also occur,with potential effects on therapeut
43、ic outcomes.Further investigations into the immunomodulatory effects of apoptotic MSCs,particularly with regard to the role of efferocytosis,will be important for the optimization of MSC treatment strategies.Interplay between immunomodulatory factorsAs outlined above,MSCs produce various molecules w
44、ith differing immunomodulatory roles in different inflam-matory environments,raising the question of how these immunomodulatory factors are coordinated to deter-mine the MSC phenotype.For example,inflammatory cytokine-induced iNOS expression in murine MSCs can be abolished by the presence of TGF,whi
45、ch can also be secreted by MSCs,tempering the immunosuppressive potential of MSCs59.By contrast,PGE2 and IDO can act synergistically in human MSCs to inhibit NK cell activa-tion109.Interestingly,studies involving the deletion of IDO in human MSCs have shown that IDO can regulate the expression of TS
46、G6(reF.34).Consequently,administration of human MSCs inhibited neutrophil and macrophage accumulation in mouse models of acute lung injury and peritonitis through IDO metabolite-induced production of TSG634.The effects of IDO on TSG6 expression are mediated by the tryptophan metabolite kynurenic aci
47、d,which activates the aryl hydrocarbon receptor(AhR)in human MSCs,which then binds to the TSG6 promoter,leading to transactivation of TSG6(reF.34).Thus,availa-ble data suggest the existence of cross communication between immunoregulatory molecules released by MSCs,which fine-tunes the phenotype of t
48、he MSCs.Clinical applications of MSCsThe immunomodulatory and homeostatic effects of MSCs suggest that they offer a strategy to regulate inflam-mation and promote repair of damaged tissues in both acute and chronic inflammatory diseases.To date,over 700 clinical trials involving MSCs have been regis
49、tered with ClinicalTrials.gov.Of these,218 trials that aimed to provide a preliminarily evaluation of the safety and effi-cacy of MSCs in various disease states,including GvHD,transplant rejection,autoimmune diseases,organ inju-ries and cardiovascular diseases,have been completed(TABles1,2).Although
50、 large,rigorously designed trials are yet to be completed,the available data provide proof of concept for the potential of MSCs in treating or ame-liorating inflammatory diseases.Below,we discuss some of the preclinical and clinical evidence supporting a role for MSCs in GvHD and inflammatory kidney