The immune suppressive and anti-inflammatory capabilities of bone marrow-derived mesenchymal stromal cells (MSCs) represent an innovative new tool in regenerative medicine and immune regulation. The potent immune suppressive ability of MSC over T cells, dendritic cells, and natural killer cells has been extensively characterized, however, the effect of MSC on B cell function has not yet been clarified. In this study, the direct effect of MSC on peripheral blood B cell function is defined and the mechanism utilized by MSC in enhancing B cell survival in vitro identified. Human MSC supported the activation, proliferation, and survival of purified CD19+ B cells through a cell contact-dependent mechanism. These effects were not mediated through B cell activating factor or notch signaling. However, cell contact between MSC and B cells resulted in increased production of vascular endothelial growth factor (VEGF) by MSC facilitating AKT phosphorylation within the B cell and inhibiting caspase 3-mediated apoptosis. Blocking studies demonstrated that this cell contact-dependent effect was not dependent on signaling through CXCR4-CXCL12 or through the epidermal growth factor receptor (EGFR). These results suggest that direct cell contact between MSC and B cells supports B cell viability and function, suggesting that MSC may not represent a suitable therapy for B cell-mediated disease.
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References
1.
BarryFP, MurphyJM, EnglishK and MahonBP. (2005). Immunogenicity of adult mesenchymal stem cells: lessons from the fetal allograft. Stem Cells Dev, 14:252–265.
2.
da Silva MeirellesL, CaplanAI and NardiNB. (2008). In search of the in vivo identity of mesenchymal stem cells. Stem Cells, 26:2287–2299.
3.
PittengerMF, MackayAM, BeckSC, JaiswalRK, DouglasR, MoscaJD, MoormanMA, SimonettiDW, CraigS and MarshakDR. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284:143–147.
4.
EnglishK, BarryFP, Field-CorbettCP and MahonBP. (2007). IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett, 110:91–100.
5.
TobinLM, HealyME, EnglishK and MahonBP. (2013). Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease. Clin Exp Immunol, 172:333–348.
6.
WangQ, SunB, WangD, JiY, KongQ, WangG, WangJ, ZhaoW, JinL and LiH. (2008). Murine bone marrow mesenchymal stem cells cause mature dendritic cells to promote T-cell tolerance. Scand J Immunol, 68:607–615.
7.
EnglishK, BarryFP and MahonBP. (2008). Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation. Immunol Lett, 115:50–58.
8.
SpaggiariGM, AbdelrazikH, BecchettiF and MorettaL. (2009). MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood, 113:6576–6583.
9.
SpaggiariGM, CapobiancoA, AbdelrazikH, BecchettiF, MingariMC and MorettaL. (2008). Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood, 111:1327–1333.
10.
NooneC, KihmA, EnglishK, O'DeaS and MahonBP. (2013). IFN-γ stimulated human umbilical-tissue-derived cells potently suppress NK activation and resist NK-mediated cytotoxicity in vitro. Stem Cells Dev, 22:3003–3014.
11.
RyanJM, BarryF, MurphyJM and MahonBP. (2007). Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol, 149:353–363.
12.
PolchertD, SobinskyJ, DouglasG, KiddM, MoadsiriA, ReinaE, GenrichK, MehrotraS, SettyS, SmithB and BartholomewA. (2008). IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol, 38:1745–1755.
TaberaS, Pérez-SimónJA, Díez-CampeloM, Sánchez-AbarcaLI, BlancoB, LópezA, BenitoA, OcioE, Sánchez-GuijoFM, CañizoC and San MiguelJF. (2008). The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica, 93:1301–1309.
15.
RasmussonI, Le BlancK, SundbergB and RingdénO. (2007). Mesenchymal stem cells stimulate antibody secretion in human B cells. Scand J Immunol, 65:336–343.
16.
TraggiaiE, VolpiS, SchenaF, GattornoM, FerlitoF, MorettaL and MartiniA. (2008). Bone marrow-derived mesenchymal stem cells induce both polyclonal expansion and differentiation of B cells isolated from healthy donors and systemic lupus erythematosus patients. Stem Cells, 26:562–569.
17.
ComoliP, GinevriF, MaccarioR, AvanziniMA, MarconiM, GroffA, CometaA, CioniM, PorrettiL, et al. (2008). Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation. Nephrol Dial Transplant, 23:1196–1202.
18.
FranquesaM, HoogduijnMJ, BestardO and GrinyóJM. (2012). Immunomodulatory effect of mesenchymal stem cells on B cells. Front Immunol, 3:212.
19.
KielMJ and MorrisonSJ. (2008). Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol, 8:290–301.
20.
MacLennanICM. (1995). Autoimmunity: deletion of autoreactive B cells. Curr Biol, 5:103–106.
21.
FranquesaM, MensahFK, HuizingaR, StriniT, BoonL, LombardoE, DelaRosaO, LamanJD, GrinyoJM, et al. (2014). Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells, 33:880–891.
22.
RosadoMM, BernardoME, ScarsellaM, ConfortiA, GiordaE, BiaginiS, CascioliS, RossiF, GuzzoI, et al. (2014). Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev, 24:93–103.
23.
BarryFP and MurphyJM. (2004). Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol, 36:568–584.
24.
PieperK, GrimbacherB and EibelH. (2013). B-cell biology and development. J Allergy Clin Immunol, 131:959–971.
25.
Méndez-FerrerS, MichurinaTV, FerraroF, MazloomAR, MacarthurBD, LiraS, ScaddenDT, Ma'ayanA, EnikolopovGN and FrenettePS. (2010). Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature, 466:829–834.
26.
SchneiderP, MacKayF, SteinerV, HofmannK, BodmerJL, HollerN, AmbroseC, LawtonP, BixlerS, et al. (1999). BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med, 189:1747–1756.
27.
WangH, ChenT, DingT, ZhuP, XuX, YuL and XieY. (2011). Adipogenic differentiation alters the immunoregulatory property of mesenchymal stem cells through BAFF secretion. Hematology, 16:313–323.
28.
RadtkeF, WilsonA and MacDonaldHR. (2004). Notch signaling in T- and B-cell development. Curr Opin Immunol, 16:174–179.
29.
ThomasM, CalamitoM, SrivastavaB, MaillardI, PearWS and AllmanD. (2007). Notch activity synergizes with B-cell-receptor and CD40 signaling to enhance B-cell activation. Blood, 109:3342–3350.
30.
Nwabo KamdjeAH, MosnaF, BifariF, LisiV, BassiG, MalpeliG, RicciardiM, PerbelliniO, ScupoliMT, PizzoloG and KramperaM. (2011). Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells. Blood, 118:380–389.
31.
ChenL, ZhangW, YueH, HanQ, ChenB, ShiM, LiJ, LiB, YouS, ShiY and ZhaoRC. (2007). Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells. Stem Cells Dev, 16:719–731.
32.
Del PapaB, SportolettiP, CecchiniD, RosatiE, BalucaniC, BaldoniS, FettucciariK, MarconiP, MartelliMF, FalzettiF and Di IanniM. (2013). Notch1 modulates mesenchymal stem cells mediated regulatory T-cell induction. Eur J Immunol, 43:182–187.
33.
CahillEF, TobinLM, CartyF, MahonBP and EnglishK. (2015). Jagged-1 is required for the expansion of CD4(+) CD25(+) FoxP3(+) regulatory T cells and tolerogenic dendritic cells by murine mesenchymal stromal cells. Stem Cell Res Ther, 6:19.
34.
GospodarowiczD and LauK. (1989). Pituitary follicular cells secrete both vascular endothelial growth factor and follistatin. Biochem Biophys Res Commun, 165:292–298.
35.
BeckermannBM, KallifatidisG, GrothA, FrommholdD, ApelA, MatternJ, SalnikovAV, MoldenhauerG, WagnerW, et al. (2008). VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer, 99:622–631.
36.
GuptaK, KshirsagarS, LiW, GuiL, RamakrishnanS, GuptaP, LawPY and HebbelRP. (1999). VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res, 247:495–504.
ZhouH, LiXM, MeinkothJ and PittmanRN. (2000). Akt regulates cell survival and apoptosis at a postmitochondrial level. J Cell Biol, 151:483–494.
39.
NieY, WaiteJ, BrewerF, SunshineMJ, LittmanDR and ZouYR. (2004). The role of CXCR4 in maintaining peripheral B cell compartments and humoral immunity. J Exp Med, 200:1145–1156.
40.
LiangZ, BrooksJ, WillardM, LiangK, YoonY, KangS and ShimH. (2007). CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem Biophys Res Commun, 359:716–722.
41.
De LucaA, GalloM, AldinucciD, RibattiD, LamuraL, D'AlessioA, De FilippiR, PintoA and NormannoN. (2011). Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells. J Cell Physiol, 226:2131–2138.
42.
DuijvesteinM, VosACW, RoelofsH, WildenbergME, WendrichBB, VerspagetHW, Kooy-WinkelaarEMC, KoningF, ZwagingaJJ, et al. (2010). Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. Gut, 59:1662–1669.
43.
HareJM, TraverseJH, HenryTD, DibN, StrumpfRK, SchulmanSP, GerstenblithG, DeMariaAN, DenktasAE, et al. (2009). A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol, 54:2277–2286.
44.
PrasadVK, LucasKG, KleinerGI, TalanoJAM, JacobsohnD, BroadwaterG, MonroyR and KurtzbergJ. (2011). Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (ProchymalTM) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant, 17:534–541.
45.
SchwarzS, HussR, Schulz-SiegmundM, VogelB, BrandauS, LangS and RotterN. (2014). Bone marrow-derived mesenchymal stem cells migrate to healthy and damaged salivary glands following stem cell infusion. Int J Oral Sci, 6:154–161.
46.
YoudM, BlickarzC, WoodworthL, TouzjianT, EdlingA, TedstoneJ, RuzekM, TuboR, KaplanJ and LodieT. (2010). Allogeneic mesenchymal stem cells do not protect NZBxNZW F1 mice from developing lupus disease. Clin Exp Immunol, 161:176–186.
47.
EttingerR, SimsGP, FairhurstAM, RobbinsR, da SilvaYS, SpolskiR, LeonardWJ and LipskyPE. (2005). IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol, 175:7867–7879.
48.
TokoyodaK, ZehentmeierS, HegazyAN, AlbrechtI, GrünJR, LöhningM and RadbruchA. (2009). Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity, 30:721–730.
49.
UccelliA, MorettaL and PistoiaV. (2006). Immunoregulatory function of mesenchymal stem cells. Eur J Immunol, 36:2566–2573.
50.
FiúzaUM and AriasAM. (2007). Cell and molecular biology of Notch. J Endocrinol, 194:459–474.
51.
LeungD, CachianesG, KuangW, GoeddelD and FerraraN. (1989). Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 246:1306–1309.
52.
KeckP, HauserS, KriviG, SanzoK, WarrenT, FederJ and ConnollyD. (1989). Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science, 246:1309–1312.
53.
SpyridopoulosI, BrogiE, KearneyM, SullivanAB, CetruloC, IsnerJM and LosordoDW. (1997). Vascular endothelial growth factor inhibits endothelial cell apoptosis induced by tumor necrosis factor-alpha: balance between growth and death signals. J Mol Cell Cardiol, 29:1321–1330.
54.
NakaoN, NakayamaT, YahataT, MugurumaY, SaitoS, MiyataY, YamamotoK and NaoeT. (2010). Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo: advantages over bone marrow-derived mesenchymal stem cells. Am J Pathol, 177:547–554.
55.
WellsA. (1999). EGF receptor. Int J Biochem Cell Biol, 31:637–643.
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