Hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are both adult stem cells residing in the bone marrow. MSCs interact with HSCs, they stimulate and enhance the proliferation of HSCs by secreting regulatory molecules and cytokines, providing a specialized microenvironment for controlling the process of hematopoiesis. In this paper we discuss how MSCs contribute to HSC niche, maintain the stemness and proliferation of HSCs, and support HSC transplantation.
1. Introduction
Hematopoietic stem cells (HSCs) are rare cells residing in the bone marrow (BM; 1 in 104 to 1 in 108 of BM nucleated cells), and they are progenitors that become progressively restricted to several or single lineages. These progenitors yield blood precursors devoted to unilineage differentiation and the production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells (monocyte/macrophage and neutrophil), and lymphocytes [1, 2]. CD34 surface antigen (CD34+) is commonly used as a marker to identify and quantify the population of progenitor cells [3], according to which, sorting HSCs from BM, peripheral blood (PB), and umbilical cord (UC)/placenta blood is relatively simple and practical [2, 4–6]. Human HSCs are known to exhibit CD34+, Thy1+, CD38lo/−, Ckit−/lo, CD105+, and Lin− phenotype. However, there is no general agreement on the association between any combination of these antigenic properties and function of stem cells [3, 6]. HSCs depend on their microenvironment, the niche, for regulating self-renewal and differentiation [7]. For instance, the disruption of BMP pathway can increase the numbers of osteoblasts and HSCs [8, 9], and the chemokine CXCL12 regulates the cyclical release and the migration of HSCs [10, 11]. Activation of β-catenin enforces HSCs enter cell cycle, thus leading to exhaustion of the long-term stem cell pool [12–14]. These findings suggest that signaling pathways and cellular interactions regulate the BM niche for HSCs. Besides, hypoxia regulate hematopoiesis in BM by maintaining important HSC functions and the interplay between HSCs and neighboring cells [15, 16].
Plating studies indicate that mesenchymal stem cells (MSCs) are present as a rare population of cells in the BM. They represent approximately 0.001% to 0.01% of the nucleated cells, about 10-fold less abundant than HSCs, but MSCs can be readily grown in culture [17]. Though predominantly residing in the BM, MSCs also present similar but not identical features in many other tissues such as blood, placenta, dental pulp, and adipose tissue. MSCs have the potential to differentiate into multiple phenotypes such as osteoblasts, chondrocytes, adipocytes, neural cells, and probably other cell lineages [18–21]. International Society for Cellular Therapy (ISCT) has provided the following minimum criteria for defining multipotent mesenchymal stromal cells as follows: plastic-adherent under standard culture conditions; express CD105, CD73, and CD90 and lack expression of CD45, CD34, CD14, or CD11b, CD79 or CD19 and HLA-DR, and must differentiate into osteoblasts, adipocytes, and chondroblasts in vitro [22].
BM has received the most attention because it carries MSCs as well as HSCs. Evidence indicates that MSCs are key component of the HSC niche in the BM where these two distinct stem cell populations arrange closely, ensuring hematopoietic and skeletal homeostasis [18]. MSCs interact with HSCs, secreting chemokines that contribute to HSC niche and support long-term growth of HSCs [23, 24]. MSCs can be cotransplanted with HSCs to improve their engraftment [25–27] (Table 1).
The cytokines secreted by MSCs that regulate HSCs.
Cytokines
Function
References
CXCL12
Regulate the adhesion, expansion, migration, and homing of HSCs
[10, 11, 28–32]
(SDF-1)
Reduce the production of inflammatory cytokines and chemokines
[33]
FL
Maintain HSC proliferation and self-renewal, regulate hematopoietic growth
[28]
IL-6, TPO
Influence HSC proliferation and differentiation
[29, 34]
GM-CSF
Regulate HSC engraftment
[35]
SCF
Maintain HSC proliferation and self-renewal
Regulate hematopoietic growth
[28, 36]
Regulate HSC engraftment
[35]
VCAM1, E-selectin, collagen I, fibronectin
Regulate HSC homing and adhesion
[35, 37]
2. Mesenchymal Stem Cells Contribute to Hematopoietic Stem Cell Niche
The term “niche” for the specific HSC BM microenvironment was first coined in 1978, proposing that HSCs are in intimate contact with the bone, which was responsible for the apparently unlimited capacity of HSCs’ proliferation and the inhibition of HSCs’ maturation [38]. Niches exist within the BM which preserve specific aspects of hematopoiesis, such as HSC survival, self-renewal, and differentiation, supporting the maintenance of the blood system under normal and stressed conditions [39]. Research has made it increasingly clear that the stem cell niches provide a microenvironment which is important in protecting the self-renewing, undifferentiated state of their residents [40]. Three types of HSC niches have been hypothesized, defined according to the HSC uniformity [18, 41]. Two of these proposed niches are provided by cells directly descending from MSCs: the osteoblastic niche, where HSCs reside in close contact with endosteal cells [8], and the reticular stromal niche, where HSCs reside in close contact with stromal cells which are also known as mural cells or pericytes, the smooth muscle cells lining arteriolar side of the sinusoids [42]. The third proposed niche is the vascular/sinusoidal niche, where HSCs reside in direct contact with endothelial cells in the venous side of the sinusoids [43]. It is well known that HSC circulation involves HSCs leaving the BM, entering the vascular system (mobilization), and returning to the BM (homing) [44, 45]. The BM vascular structure provides a barrier between the hematopoietic compartment and the peripheral circulation. Most primitive HSCs remain physiologically quiescent within the BM niche; however, a portion of HSCs leave this resting pool and start the process of mobilization [39, 46–48].
Studies showed that both mouse and human osteoblast cell lines secreted a large number of cytokines that promote the proliferation of haematopoietic cells in culture, proving that cells involved in bone formation have stem-cell-supporting activity [49, 50]. MSCs reside in the bone cavity and are proposed to give rise to the majority of marrow stromal cell lineages, including chondrocytes, osteoblasts, and adipocytes, as suggested in numerous studies [48–50]. MSCs and HSCs form a structurally unique niche in the BM, which is regulated by local input from the surrounding microenvironment, and long-distance cues from hormones and the autonomic nervous system [51]. MSCs isolated from BM produce several growth factors and chemokines, such as CXCL12 (SDF-1), stem cell factor (SCF), Flt-3 ligand (FL), thrombopoietin (TPO), interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF), macrophage colony-stimulating factor (M-CSF), tumor necrosis factor- (TNF-) α, and transforming growth factor- (TGF-) β1 [28, 52–54]. HSCs are reduced in the BM after the depletion of MSCs, owing at least in part to mobilization towards extramedullary sites [51]. Loss of SCF from supporting cells or the receptor in HSCs leads to hematopoietic failure, indicating MSCs play an essential role in HSC niche function [36]. SCF and FL are implicated in maintaining HSC proliferation and self-renewal, regulating hematopoietic growth [28]. IL-3 or IL-6 combined with TPO signaling can influence HSC proliferation and differentiation [29, 34]. Besides, as mentioned previously, the chemokine CXCL12 interacts with its receptor CXCR4, regulates the cyclical release of HSCs, the migration of HSCs to the vascular niche from BM, and the homing of HSCs to the BM [10, 11, 29–32], and promotes adhesive interactions between HSCs and stromal cells [55]. In addition, CXCL12 chemokine signaling pathway contribute to the ex vivo expansion of HSCs [28]. Moreover, CXCL12 mediates angiogenic responses, promotes differentiation of CD34+ cells to endothelial progenitor cells, and appears to affect many other factors, including G-CSF, VEGF, and CXCL16 that relate to HSC mobilization and homing [33]. However, only β-catenin-activated MSCs but not naïve MSCs have stimulatory effect on HSC self-renewal in vivo [56].
3. The Effect of Mesenchymal Stem Cell on the Maintenance of Hematopoietic Stem Cells
Coculture of HSCs with MSCs might be an ideal method for maintaining the HSC pluripotency, because the growth or survival signals might be transferred to the HSC via adhesive molecules by modulating the cytokines and growth factor-dependent signals [57]. 5-aza-deoxycytidine (aza-D) and trichostatin A (TSA) have potent activity to maintain the stemness of HSCs, being candidate additives for HSCs ex vivo expansion, but they can also cause serious cell death [58, 59]. Koh et al. examined the effects of MSCs on the maintenance of CD34+ cells driven by aza-D and TSA in culture with the combined cytokines, and found that the total cell number of HSCs cultured with MSCs was higher in aza-D or TSA than in any culture conditions without MSCs, while most of HSCs cultured with cytokine treatment but without MSCs would lose their pluripotency and then differentiate, though they were induced to proliferate effectively [60]. It suggested that the co-culture of CD34+ cells with MSCs might not simply deliver the proliferation signals but also stemness and survival signals, and overlap the action of epigenetic regulators [57, 60].
4. Application of Bone Marrow Mesenchymal Stem Cells in Hematopoietic Stem Cell Transplantation
HSCs were primarily used in the treatment of patients with hematological malignancies. During the course of treatment, patients’ cancerous cells are first destroyed by chemo/radiotherapy and then replaced with BM or PB/G-CSF transplant from a human leukocyte antigen- (HLA-) matched donor [61, 62]. In most cases, autologous HSCs are collected prior to the treatment and reinfused into the patients, but the patient’s cancerous cells may be inadvertently collected and reinfused back into the patients along with HSCs [63]. Allogeneic marrow transplants have also been used in the treatment of hereditary blood disorders including aplastic anemia, β-thalassemia, Wiskott-Aldrich syndrome, and SCID, as well as inborn errors of metabolism disorders such as Hunter’s syndrome and Hurler’s syndrome [64–68]. One of the major challenges with HSC transplants is failure to engraft, which is mediated by donor T cells as a result of graft-versus-host disease (GVHD). Graft-versus-tumor effect of allogeneic HSC transplants may be a result of an immune reaction between donor cytotoxic T cells and patient’s malignant cells [69]. MSCs are known to interact with HSCs and immune cells, and represent potential cellular therapy to enhance allogeneic hematopoietic engraftment and prevent GVHD [70–72]. Coculture of MSCs and HSCs could cause a significantly increase in CD34+ cells [73]. Aside from BM-derived MSCs, MSCs from adipose tissue can also be applied in hematopoietic engraftment, which would be an innovative supplement for cellular therapies [74, 75].
Cotransplantation studies in animal models as well as in humans showed that primary or culture-expanded MSCs promote the engraftment of HSCs. Cotransplantation of MSCs and cord blood or mobilized peripheral blood CD34+ cells resulted in a significantly higher level of engraftment than transplantation of CD34+ cells only [35, 37, 76–81]. This enhancement was greater after cotransplantation of GM-CSF and SCF-transfected MSCs, indicating that these growth factors relate to engraftment, though the mechanism of the enhancing effect is still unknown [35]. It is likely that the ability to promote engraftment is maintained along lineage differentiation [76]. Several lines of evidence suggest that MSCs produce several essential hematopoietic growth factors, adhesion molecules [28, 52–54], and extracellular matrix (ECM) proteins (such as VCAM1, E-selectin, collagen I, and fibronectin) that are known to play an important role in HSC homing [35, 37]. Selective adhesion of progenitors and cytokines to ECM components or stromal cells then result in the colocalization of progenitors at a specific stage of differentiation with a specific array of cytokines in so-termed niches [77]. This provides a level of growth and differentiation regulation [37]. Although it would mean exposure to allogeneic donor antigens, allogeneic MSCs can provide equal enhancement of engraftment as autologous cells. Cotransplanted MSCs shift the differentiation pattern from a lymphoid to a myeloid predominance and enhance megakaryocytic engraftment [78]. The cotransplantation of HSCs and MSCs enhanced engraftment as the dose of MSCs increased whereas an excessive dose of MSCs might decrease engraftment efficiency [79]. Besides, human allogeneic MSC layers in a serum-free culture system enabled the ex vivo expansion/maintenance of human HSCs [80], which indicates that MSCs may be used as a universal and reproducible stromal feeder layer to efficiently expand and maintain human BM HSCs ex vivo [81].
MSCs produce a microenvironment supporting hematopoiesis and may contribute to immune tolerance because of low immunogenicity and the suppressive effect of alloreactivity [75, 82]. MSCs had a potent immunosuppressive effect in vivo after allogeneic stem-cell transplantations [26]. The CXCL12-α secreted by MSCs could reduce the production of a variety of inflammatory cytokines and chemokines, including IL-13, IL-3 Rβ, IL-4, IL-5, IL-9, IL-10, L-selectin, MIP-3α/β, TCA3/CCL1, TNF-a, IL-1β, lymphotactin/CXCL1, L-selectin, leptin receptor, eotaxin-2, CTACK/CCL27, CRG-2/CXCL10, and CD30L [33]. In allogeneic transplantation, the simultaneous infusion of MSCs may promote hematopoietic engraftment across the major histocompatibility complex (MHC) barrier and decrease the incidence of GVHD, even though the exact mechanisms have not been clarified [83–85]. MSCs are lack of MHC class II and most of classical costimulatory molecules [86, 87]. Moreover, MSCs directly inhibit the expansion and activation of alloreactive Tlymphocytes and this T cell-suppressive effect may have important therapeutic implications in preventing or treating acute and chronic GVHD [70]. MSCs can significantly reduced the expression of activation markers CD25 (interleukn-2 receptor), CD38, and CD69 on phytohaemagglutinin- (PHA-) stimulated lymphocytes, making allogeneic HSCs and MSCs escape from recognition by alloreactive T-cells, because the expression of CD25 (IL-2 receptor), CD38 and CD69 was unchanged. Besides, MSC suppressed the proliferation of PHA-stimulated CD3+, CD4+, and CD8+ lymphocytes [87–89]. However, MSCs inhibit naïve and memory T-cell responses to their cognate antigens by the engagement of the inhibitory molecule PD-1 while the expression of MHC molecules and the presence in culture of antigen-presenting cells (APCs) or CD4+/CD25+ regulatory T cells were not required for MSCs to inhibit preferentially [87–91]. MSCs can regulate B-cell functions including migration, proliferation, and immunoglobulin(Ig) synthesis. For example, MSCs inhibit the proliferation of B-cells by arresting them at G0/G1 phase of the cell cycle, and the production of IgM, IgA, and IgG of B-cells [88, 92]. Dendritic cells (DCs) play an important role in supporting antigen-specific CD4+ T-cell proliferation and modulating diverse T-cell responses including GVHD [93]. MSCs can inhibit the differentiation of mature DCs from HSCs by arresting them at the precursor stage, interfere with DC antigen presentation, prevent DC migration ability, and induce DC apoptosis by downregulate TNF-α and TGF-β1 levels and upregulated IL-6 levels [93–95]. IFN-γ, which is produced by donor T-cells in response to antigen recognition, displays natural cytolytic activity against the cells missing markers of self-MHC class I, serves as an initiating stimulus for MSC immunosuppressive activity in vivo [88]. This indicates that the exposure to concentrated amounts of IFN-γ of MSCs can stimulate MSCs to exhibit induction of class II molecule expression, to prevent GVHD and provide the basis for a new potential strategy in prevention of GVHD [87–89, 96]. There is also evidences that MSCs can inhibit the IL-2-induced proliferation of natural killer (NK) cells by producing prostaglandin E2 (PGE2), a product of arachidonic acid metabolism that acts as a powerful immune suppressant, and inhibits T-cell mitogenesis and IL-2 production [88, 97, 98] (Figure 1).
MSCs interact with immune cells, representing potential cellular therapy to enhance allogeneic hematopoietic engraftment and prevent GVHD. MSCs reduced the expression of activation markers CD25, CD38 and CD69 on PHA-stimulated lymphocytes, making allogeneic HSCs and MSCs escape from recognition of alloreactive T-cells. MSCs suppressed the proliferation of PHA-stimulated CD3+, CD4+ and CD8+ lymphocytes. MSCs inhibit naïve and memory T-cell responses to their cognate antigens by the engagement of the inhibitory molecule PD-1. MSCs inhibit the proliferation of B-cells and the differentiation of mature DCs from HSCs. MSCs induce DC apoptosis by downregulate TNF-α and TGF-β1 levels and upregulated IL-6 levels. MSCs inhibit the IL-2-induced proliferation of NK cells by producing PGE2. IFN-γ can stimulate MSCs to exhibit induction of class II molecule expression to prevent GVHD.
5. Conclusion
Lines of evidence have indicated that MSCs are capable of supporting the expansion and differentiation of HSCs and enhancing hematopoietic engraftment in the past two decades, but the exact mechanisms by how MSCs support HSCs are still unclear. MSCs may affect HSCs by producing growth factors and chemokines that take parts in signaling pathways regulating HSCs. Meanwhile, HSCs interact with MSCs though this has been less understood. MSCs can home to injured tissues when coinfused with HSCs [99]. A better understanding of the interaction between MSCs and HSCs will substantially ultimately help develop novel therapies for hematopoietic diseases.
Acknowledgment
This paper was supported by grants from Natural Science Foundation of China (nos. 30871273, 30971496, and U1032003) and from Shenzhen (JC201005280597A) to Y. Wu.
OrkinS. H.ZonL. I.Hematopoiesis: an evolving paradigm for stem cell biology200813246316442-s2.0-3934909652610.1016/j.cell.2008.01.025Group SCTCAllogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials20052322507450872-s2.0-2464450367010.1200/JCO.2005.09.020MurrayL.ChenB.GalyA.ChenS.TushinskiR.UchidaN.NegrinR.TricotG.JagannathS.VesoleD.BarlogieB.HoffmanR.TsukamotoA.Enrichment of human hematopoietic stem cell activity in the CD34+Thy- 1+Lin subpopulation from mobilized peripheral blood19958523683782-s2.0-0028942103FlomenbergN.DevineS. M.DiPersioJ. F.LiesveldJ. L.McCartyJ. M.RowleyS. D.VesoleD. H.BadelK.CalandraG.The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone20051065186718742-s2.0-2394452535210.1182/blood-2005-02-0468GluckmanE.BroxmeyerH. A.AuerbachA. D.FriedmanH. S.DouglasG. W.DevergieA.EsperouH.ThierryD.SocieG.LehnP.CooperS.EnglishD.KurtzbergJ.BardJ.BoyseE. A.Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling198932117117411782-s2.0-0024396816PierelliL.ScambiaG.BonannoG.RutellaS.PuggioniP.BattagliaA.MozzettiS.MaroneM.MenichellaG.RumiC.MancusoS.LeoneG.CD34+/CD105+ cells are enriched in primitive circulating progenitors residing in the G0 phase of the cell cycle and contain all bone marrow and cord blood CD34+/CD38low/- precursors200010836106202-s2.0-003411722710.1046/j.1365-2141.2000.01869.xMorrisonS. J.SpradlingA. C.Stem cells and niches: mechanisms that promote stem cell maintenance throughout life200813245986112-s2.0-3914914403410.1016/j.cell.2008.01.038CalviL. M.AdamsG. B.WeibrechtK. W.WeberJ. M.OlsonD. P.KnightM. C.MartinR. P.SchipaniE.DivietiP.BringhurstF. R.MilnerL. A.KronenbergH. M.ScaddenD. T.Osteoblastic cells regulate the haematopoietic stem cell niche200342569608418462-s2.0-024226852410.1038/nature02040ZhangJ. W.NiuC.YeL.HuangH.HeX.TongW. G.RossJ.HaugJ.JohnsonT.FengJ. Q.HarrisS.WiedemannL. M.MishinaY.LiL.Identification of the haematopoietic stem cell niche and control of the niche size200342569608368412-s2.0-024236322510.1038/nature02041Méndez-FerrerS.LucasD.BattistaM.FrenetteP. S.Haematopoietic stem cell release is regulated by circadian oscillations200845271864424472-s2.0-3974916492010.1038/nature06685SugiyamaT.KoharaH.NodaM.NagasawaT.Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches20062569779882-s2.0-3384544593910.1016/j.immuni.2006.10.016SchellerM.HuelskenJ.RosenbauerF.TaketoM. M.BirchmeierW.TenenD. G.LeutzA.Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation2006710102110232-s2.0-3374885950910.1038/ni1387SudaT.AraiF.Wnt signaling in the niche200813257297302-s2.0-3974913957910.1016/j.cell.2008.02.017FlemingH. E.JanzenV.CelsoC. L.GuoJ.LeahyK. M.KronenbergH. M.ScaddenD. T.Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo2008232742832-s2.0-3974917839010.1016/j.stem.2008.01.003EliassonP.JönssonJ.The hematopoietic stem cell niche: low in oxygen but a nice place to be2010222117222-s2.0-7394912124910.1002/jcp.21908HosokawaK.AraiF.YoshiharaH.NakamuraY.GomeiY.IwasakiH.MiyamotoK.ShimaH.ItoK.SudaT.Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction200736335785832-s2.0-3484886752110.1016/j.bbrc.2007.09.014PittengerM. F.MartinB. J.Mesenchymal stem cells and their potential as cardiac therapeutics20049519202-s2.0-314266324110.1161/01.RES.0000135902.99383.6fValtieriM.SorrentinoA.The mesenchymal stromal cell contribution to homeostasis200821722963002-s2.0-5144909259010.1002/jcp.21521KöglerG.SenskenS.AireyJ. A.TrappT.MüschenM.FeldhahnN.LiedtkeS.SorgR. V.FischerJ.RosenbaumC.GreschatS.KnipperA.BenderJ.DegistiriciÖ. ̈.GaoJ.CaplanA. I.CollettiE. J.Almeida-PoradaG.MüllerH. W.ZanjaniE.WernetP.A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential200420021231352-s2.0-324275583410.1084/jem.20040440TondreauT.LagneauxL.DejenefleM.MassyM.MortierC.DelforgeA.BronD.Bone marrow-derived mesenchymal stem cells already express specific neural proteins before any differentiation20047273193262-s2.0-1814438014210.1111/j.1432-0436.2004.07207003.xDennisJ. E.CharbordP.Origin and differentiation of human and murine stroma20022032052142-s2.0-0036244446DominiciM.Le BlancK.MuellerI.Slaper-CortenbachI.MariniF. C.KrauseD. S.DeansR. J.KeatingA.ProckopD. J.HorwitzE. M.Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement2006843153172-s2.0-3374771324610.1080/14653240600855905ImaiE.ItoT.Can bone marrow differentiate into renal cells?200217107907942-s2.0-003695286210.1007/s00467-002-0949-4MohantyS. T.KottamL.GambardellaA.NicklinM. J.CoultonL.HughesD.WilsonA. G.CroucherP. I.BellantuonoI.Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis2010124R1492-s2.0-7795479588610.1186/ar3098KoçO. N.GersonS. L.CooperB. W.DyhouseS. M.HaynesworthS. E.CaplanA. I.LazarusH. M.Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy20001823073162-s2.0-0033977382BlancK. L.RasmussonI.SundbergB.GötherströmC.HassanM.UzunelM.RingdénO.Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells20043639419143914412-s2.0-234248252610.1016/S0140-6736(04)16104-7AggarwalS.PittengerM. F.Human mesenchymal stem cells modulate allogeneic immune cell responses20051054181518222-s2.0-1354424960610.1182/blood-2004-04-1559MishimaS.NagaiA.AbdullahS.MatsudaC.TaketaniT.KumakuraS.ShibataH.IshikuraH.KimS. U.MasudaJ.Effective ex vivo expansion of hematopoietic stem cells using osteoblast-differentiated mesenchymal stem cells is CXCL12 dependent20108465385462-s2.0-7795266044010.1111/j.1600-0609.2010.01419.xZhangJ.LiL.Stem cell niche: microenvironment and beyond200828315949995032-s2.0-4434909692310.1074/jbc.R700043200BurnessM. L.SipkinsD. A.The stem cell niche in health and malignancy20102021071152-s2.0-7795378254310.1016/j.semcancer.2010.05.006LamB. S.AdamsG. B.Hematopoietic stem cell lodgment in the adult bone marrow stem cell niche20103265515582-s2.0-7834927952610.1111/j.1751-553X.2010.01250.xBurnsJ. M.SummersB. C.WangY.MelikianA.BerahovichR.MiaoZ.PenfoldM. E. T.SunshineM. J.LittmanD. R.KuoC. J.WeiK.McMasterB. E.WrightK.HowardM. C.SchallT. J.A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development20062039220122132-s2.0-3374847483810.1084/jem.20052144ThevenotP. T.NairA. M.ShenJ.LotfiP.KoC. Y.TangL.The effect of incorporation of SDF-1α into PLGA scaffolds on stem cell recruitment and the inflammatory response20103114399740082-s2.0-7764927553510.1016/j.biomaterials.2010.01.144RappoldI.WattS. M.KusadasiN.Rose-JohnS.HatzfeldJ.PloemacherR. E.Gp130-signaling synergizes with FL and TPO for the long-term expansion of cord blood progenitors19991312203620482-s2.0-0032760571HanJ. Y.GohR. Y.SeoS. Y.Cotransplantation of cord blood hematopoietic stem cells and culture-expanded and GM-CSF-/SCF-transfected mesenchymal stem cells in SCID mice20072222422472-s2.0-34248517207BernsteinA.ForresterL.ReithA. D.DubreuilP.RottapelR.The murine W/c-kit and steel loci and the control of hematopoiesis19912821381422-s2.0-0025732066VerfaillieM.Adhesion receptors as regulators of the hematopoietic process1998928260926122-s2.0-0032532648SchofieldR.The relationship between the spleen colony-forming cell and the haemopoietic stem cell197841-27252-s2.0-0018102359GarrettR. W.EmersonS. G.Bone and blood vessels: the hard and the soft of hematopoietic stem cell niches200910545035062-s2.0-6604914985110.1016/j.stem.2009.05.011FuchsE.TumbarT.GuaschG.Socializing with the neighbors: stem cells and their niche200411667697782-s2.0-164260395110.1016/S0092-8674(04)00255-7FierroF.IllmerT.JingD.SchleyerE.EhningerG.BoxbergerS.BornhäuserM.Inhibition of platelet-derived growth factor receptor-β by imatinib mesylate suppresses proliferation and alters differentiation of human mesenchymal stem cells in vitro20074033553662-s2.0-3424902538110.1111/j.1365-2184.2007.00438.xSacchettiB.FunariA.MichienziS.Di CesareS.PiersantiS.SaggioI.TagliaficoE.FerrariS.RobeyP. G.RiminucciM.BiancoP.Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment200713123243362-s2.0-3534892168210.1016/j.cell.2007.08.025KielM. J.YilmazO. H.IwashitaT.YilmazO. H.TerhorstC.MorrisonS. J.SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells20051217110911212-s2.0-2124446342610.1016/j.cell.2005.05.026YinT.LiL.The stem cell niches in bone20061165119512012-s2.0-3364643530910.1172/JCI28568RaaijmakersM. H.Regulating traffic in the hematopoietic stem cell niche2010959143914412-s2.0-7795679802010.3324/haematol.2010.027342HeissigB.HattoriK.DiasS.FriedrichM.FerrisB.HackettN. R.CrystalR. G.BesmerP.LydenD.MooreM. A. S.WerbZ.RafiiS.Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of Kit-ligand200210956256372-s2.0-1844438945110.1016/S0092-8674(02)00754-7AraiF.HiraoA.OhmuraM.SatoH.MatsuokaS.TakuboK.ItoK.KohG. Y.SudaT.Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche200411821491612-s2.0-324266914510.1016/j.cell.2004.07.004XieY.YinT.WiegraebeW.Detection of functional haematopoietic stem cell niche using real-time imaging20094577225971012-s2.0-5814925028710.1038/nature07639TaichmanR. S.EmersonS. G.The role of osteoblasts in the hematopoietic microenvironment19981617152-s2.0-0031883380MugurumaY.YahataT.MiyatakeH.SatoT.UnoT.ItohJ.KatoS.ItoM.HottaT.AndoK.Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment20061075187818872-s2.0-3334447851310.1182/blood-2005-06-2211Méndez-FerrerS.MichurinaT. V.FerraroF.MazloomA. R.MacArthurB. D.LiraS. A.ScaddenD. T.Mag'AyanA.EnikolopovG. N.FrenetteP. S.Mesenchymal and haematopoietic stem cells form a unique bone marrow niche2010466128298342-s2.0-7795564619310.1038/nature09262MajumdarM. K.ThiedeM. A.HaynesworthS. E.BruderS. P.GersonS. L.Human marrow-derived mesenchymal stem cells (MSCs) express hematopoietic cytokines and support long-term hematopoiesis when differentiated toward stromal and osteogenic lineages2000968418482-s2.0-003448977210.1089/152581600750062264ShiL.HuL. H.The normal flora may contribute to the quantitative preponderance of myeloid cells under physiological conditions201121121411432-s2.0-7865017690710.1016/j.mehy.2010.09.004JeltschK. S.RadkeT. F.LaufsS.GiordanoF. A.AllgayerH.WenzF.ZellerW. J.KöglerG.FruehaufS.MaierP.Unrestricted somatic stem cells: interaction with CD34+ cells in vitro and in vivo, expression of homing genes and exclusion of tumorigenic potential201113335736510.3109/14653249.2010.523076RatliffB. B.SinghN.YasudaK.ParkH. C.AddabboF.GhalyT.RajdevM.JasminJ. F.PlotkinM.LisantiM. P.GoligorskyM. S.Mesenchymal stem cells, used as bait, disclose tissue binding sites201017728738832-s2.0-7795728547410.2353/ajpath.2010.090984AhnJ. Y.ParkG.ShimJ. S.LeeJ. W.OhI. H.Intramarrow injection of β-catenin-activated, but not naïve mesenchymal stromal cells stimulates self-renewal of hematopoietic stem cells in bone marrow20104221221312-s2.0-7764920755510.3858/emm.2010.42.2.014TavassoliM.FriedensteinA.Hemopoietic stromal microenvironment19831521952032-s2.0-0020825543MarksP. A.RichonV. M.RifkindR. A.Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells20009215121012162-s2.0-0034596309WolffeA. P.JonesP. L.WadeP. A.DNA demethylation19999611589458962-s2.0-003306530210.1073/pnas.96.11.5894KohS. H.ChoiH. S.ParkE. S.KangH. J.AhnH. S.ShinH. Y.Co-culture of human CD34+ cells with mesenchymal stem cells increases the survival of CD34+ cells against the 5-aza-deoxycytidine- or trichostatin A-induced cell death20053293103910452-s2.0-1484432002310.1016/j.bbrc.2005.02.077TabataM.SatakeA.OkuraN.Long-term outcome after allogeneic bone marrow transplantation for hematological malignancies with non-remission status. Results of a single-center study of 24 patients20028110582587BallL. M.BernardoM. E.RoelofsH.LankesterA.CometaA.EgelerR. M.LocatelliF.FibbeW. E.Cotransplantation of ex vivo-expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation20071107276427672-s2.0-3494889266810.1182/blood-2007-04-087056Hombach-KlonischS.PanigrahiS.RashediI.SeifertA.AlbertiE.PocarP.KurpiszM.Schulze-OsthoffK.MacKiewiczA.LosM.Adult stem cells and their trans-differentiation potential-perspectives and therapeutic applications20088612130113142-s2.0-5694909002410.1007/s00109-008-0383-6IannoneR.CasellaJ. F.FuchsE. J.ChenA. R.JonesR. J.WoolfreyA.AmylonM.SullivanK. M.StorbR. F.WaltersM. C.Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and β-thalassemia2003985195282-s2.0-1214428937910.1016/S1083-8791(03)00192-7PaiS. Y.DeMartiisD.ForinoC.CavagniniS.LanfranchiA.GilianiS.MorattoD.MazzaC.PortaF.ImbertiL.NotarangeloL. D.MazzolariE.Stem cell transplantation for the Wiskott-Aldrich syndrome: a single-center experience confirms efficacy of matched unrelated donor transplantation200638106716792-s2.0-3375054602710.1038/sj.bmt.1705512PetersC.KrivitW.Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome)20002510109710992-s2.0-0034183048SalernoM.BusielloR.EspositoV.CosentiniE.AdrianiM.SelleriC.RotoliB.PignataC.Allogeneic bone marrow transplantation restores IGF-I production and linear growth in a γ-SCID patient with abnormal growth hormone receptor signaling20043377737752-s2.0-1344424944710.1038/sj.bmt.1704421StabaS. L.EscolarM. L.PoeM.KimY.MartinP. L.SzabolcsP.Allison-ThackerJ.WoodS.WengerD. A.RubinsteinP.HopwoodJ. J.KrivitW.KurtzbergJ.Cord-blood transplants from unrelated donors in patients with hurler's syndrome200435019196019692-s2.0-234253510310.1056/NEJMoa032613KurokawaT.FischerK.BertzH.HoegerleS.FinkeJ.MackensenA.In vitro and in vivo characterization of graft-versus-tumor responses in melanoma patients after allogeneic peripheral blood stem cell transplantation2002101152602-s2.0-003672278810.1002/ijc.10555MaitraB.SzekelyE.GjiniK.LaughlinM. J.DennisJ.HaynesworthS. E.KoçO. N.Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation20043365976042-s2.0-184248315310.1038/sj.bmt.1704400ResnickI.StepenskyP.ElkinG.BarkatzC.GurevichO.PrigozhinaT.PikarskyE.WaldmanE.AmarA.SamuelS.ShapiraM.WeintraubM.OrR.MSC for the improvement of hematopoietic engraftment20104536056062-s2.0-7794941826510.1038/bmt.2009.199El BacklyR. M.CanceddaR.Bone marrow stem cells in clinical application: harnessing paracrine roles and niche mechanisms2010123265292McNieceI.HarringtonJ.TurneyJ.KellnerJ.ShpallE. J.Ex vivo expansion of cord blood mononuclear cells on mesenchymal stem cells2004643113172-s2.0-454427159810.1080/14653240410004871NakaoN.NakayamaT.YahataT.MugurumaY.SaitoS.MiyataY.YamamotoK.NaoeT.Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo201017725475542-s2.0-7795726959810.2353/ajpath.2010.091042VanikarA. V.TrivediH. L.FerozeA.KanodiaK. V.DaveS. D.ShahP. R.Effect of co-transplantation of mesenchymal stem cells and hematopoietic stem cells as compared to hematopoietic stem cell transplantation alone in renal transplantation to achieve donor hypo-responsiveness20104312252322-s2.0-7394912266810.1007/s11255-009-9659-1NoortW. A.KruisselbrinkA. B.In't AnkerP. S.KrugerM.Van BezooijenR. L.De PausR. A.HeemskerkM. H. M.LöwikC. W. G. M.FalkenburgJ. H. F.WillemzeR.FibbeW. E.Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34+ cells in NOD/SCID mice20023088708782-s2.0-1844437499210.1016/S0301-472X(02)00820-2LemischkaI. R.Microenvironmental regulation of hematopoietic stem cells199715163682-s2.0-0030722695AngelopoulouM.NovelliE.GroveJ. E.RinderH. M.CivinC.ChengL.KrauseD. S.Cotransplantation of human mesenchymal stem cells enhances human myelopoiesis and megakaryocytopoiesis in NOD/SCID mice20033154134202-s2.0-003756296810.1016/S0301-472X(03)00042-0KimD. H.YooK. H.YimY. S.Cotransplanted bone marrow derived mesenchymal stem cells (MSC) enhanced engraftment of hematopoietic stem cells in a MSC-dose dependent manner in NOD/SCID mice2006216100010042-s2.0-33845887253da SilvaC. L.GonçalvesR.CrapnellK. B.CabralJ. M.ZanjaniE. D.Almeida-PoradaG.A human stromal-based serum-free culture system supports the ex vivo expansion/maintenance of bone marrow and cord blood hematopoietic stem/progenitor cells20053378288352-s2.0-2044450080110.1016/j.exphem.2005.03.017GonçalvesR.da SilvaC. L.CabralJ. M. S.ZanjaniE. D.Almeida-PoradaG.A Stro-1+ human universal stromal feeder layer to expand/maintain human bone marrow hematopoietic stem/progenitor cells in a serum-free culture system20063410135313592-s2.0-3374852899610.1016/j.exphem.2006.05.024ChungN. G.JeongD. C.ParkS. J.ChoiB. O.ChoB.KimH. K.ChunC. S.WonJ. H.HanC. W.Cotransplantation of marrow stromal cells may prevent lethal graft-versus-host disease in major histocompatibility complex mismatched murine hematopoietic stem cell transplantation20048043703762-s2.0-944422709910.1532/IJH97.A30409GurevitchO.PrigozhinaT. B.PugatschT.SlavinS.Transplantation of allogeneic or xenogeneic bone marrow within the donor stromal microenvironment1999689136213682-s2.0-0033571585StanevskyA.ShimoniA.YerushalmiR.NaglerA.Cord blood stem cells for hematopoietic transplantation201174254332-s2.0-7795628453510.1007/s12015-010-9183-9BattiwallaM.HemattiP.Mesenchymal stem cells in hematopoietic stem cell transplantation20091155035152-s2.0-7084913280710.1080/14653240903193806SugiuraK.HishaH.IshikawaJ.AdachiY.TaketaniS.LeeS.NagahamaT.IkeharaS.Major histocompatibility complex restriction between hematopoietic stem cells and stromal cells in vitro200119146582-s2.0-0035187433AbdiR.FiorinaP.AdraC. N.AtkinsonM.SayeghM. H.Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes2008577175917672-s2.0-4824914486410.2337/db08-0180NewmanR. E.YooD.LeRouxM. A.Danilkovitch-MiagkovaA.Treatment of inflammatory diseases with mesenchymal stem cells2009821101232-s2.0-7034950166610.2174/187152809788462635KramperaM.GlennieS.DysonJ.ScottD.LaylorR.SimpsonE.DazziF.Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide20031019372237292-s2.0-003820419310.1182/blood-2002-07-2104DazziF.Marelli-BergF. M.Mesenchymal stem cells for graft-versus-host disease: close encounters with T cells2008386147914822-s2.0-4964911941710.1002/eji.200838433Le BlancK.RasmussonI.GőtherstrőmC.SeidelC.SundbergB.SundinM.RosendahlK.TammikC.RingdénO.Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes20046033073152-s2.0-434468322010.1111/j.0300-9475.2004.01483.xCorcioneA.BenvenutoF.FerrettiE.GiuntiD.CappielloV.CazzantiF.RissoM.GualandiF.MancardiG. L.PistoiaV.UccelliA.Human mesenchymal stem cells modulate B-cell functions200610713673722-s2.0-3014444092510.1182/blood-2005-07-2657EnglishK.BarryF. P.MahonB. P.Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation2008115150582-s2.0-3734907516710.1016/j.imlet.2007.10.002LaiH. Y.YangM. J.WenK. C.ChaoK. C.ShihC. C.LeeO. K.Mesenchymal stem cells negatively regulate dendritic lineage commitment of umbilical-cord-blood-derived hematopoietic stem cells: an unappreciated mechanism as immunomodulators2010169298729972-s2.0-7795608325610.1089/ten.tea.2009.0731PulavendranS.VigneshJ.RoseC.Differential anti-inflammatory and anti-fibrotic activity of transplanted mesenchymal vs. hematopoietic stem cells in carbon tetrachloride-induced liver injury in mice20101045135192-s2.0-7794954035610.1016/j.intimp.2010.01.014PolchertD.SobinskyJ.DouglasG.KiddM.MoadsiriA.ReinaE.GenrichK.MehrotraS.SettyS.SmithB.BartholomewA.IFN-γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease2008386174517552-s2.0-4964910625710.1002/eji.200738129SpaggiariG. M.CapobiancoA.BecchettiS.MingariM. C.MorettaL.Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation20061074148414902-s2.0-3264443823310.1182/blood-2005-07-2775GhannamS.BouffiC.DjouadF.JorgensenC.NoëlD.Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications2010112810.1186/scrt2ChapelA.BerthoJ. M.BensidhoumM.FouillardL.YoungR. G.FrickJ.DemarquayC.CuvelierF.MathieuE.TrompierF.DudoignonN.GermainC.MazurierC.AigueperseJ.BornemanJ.GorinN. C.GourmelonP.ThierryD.Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome2003512102810382-s2.0-194252835510.1002/jgm.452