Mesenchymal stem cells (MSCs) from rodents and humans have been shown to suppress T cells by distinct primary pathways, with nitric oxide (NO)-dependent pathways dominating in rodents and indoleamine 2,3-deoxygenase (IDO)-dependent pathways dominating in humans. However, the immune suppressive pathways utilized by canine MSC have not been thoroughly studied, nor have bone marrow-derived MSC (BM-MSC) and adipose-derived MSC (Ad-MSC) been directly compared for their immune modulatory potency or pathway utilization. Therefore, canine BM-MSC and Ad-MSC were generated in vitro and their potency in suppressing T cell proliferation and cytokine production was compared, and differential gene expression. Mechanisms of T cells suppression were also investigated for both MSC types. We found that BM-MSC and Ad-MSC were roughly equivalent in terms of their ability to suppress T cell activation. However, the two MSC types used both shared and distinct biochemical pathways to suppress T cell activation. Ad-MSC utilized TGF-β signaling pathways and adenosine signaling to suppress T cell activation, whereas BM-MSC used cyclooxygenase, TGF-β and adenosine signaling pathways to suppress T cell activation. These results indicate that canine MSC are distinct from human and rodent MSC terms of their immune suppressive pathways, relying primarily on cyclooxygenase and TGF-β pathways for T cell suppression, rather than on NO or IDO-mediated pathways.
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References
1.
GuF, WangD, ZhangH, FengX, GilkesonGS, ShiS and SunL. (2014). Allogeneic mesenchymal stem cell transplantation for lupus nephritis patients refractory to conventional therapy. Clin Rheumatol, 33:1611–1619.
2.
SunL, WangD, LiangJ, ZhangH, FengX, WangH, HuaB, LiuB, YeS, et al. (2010). Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum, 62:2467–2475.
3.
WangD, ZhangH, LiangJ, LiX, FengX, WangH, HuaB, LiuB, LuL, et al. (2013). Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Cell Transplant, 22:2267–2277.
4.
TyndallA. (2015). Mesenchymal stromal cells and rheumatic disorders. Immunol Lett, 168:201–207.
5.
TyndallA and van LaarJM. (2010). Stem cells in the treatment of inflammatory arthritis. Best Pract Res Clin Rheumatol, 24:565–574.
6.
WatermanRS, TomchuckSL, HenkleSL and BetancourtAM. (2010). A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One, 5:e10088.
7.
Le BlancK and DaviesLC. (2015). Mesenchymal stromal cells and the innate immune response. Immunol Lett, 168:140–146.
8.
KlinkerMW and WeiC-H. (2015). Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models. World J Stem Cells, 7:556–567.
9.
KoIK, KimB-G, AwadallahA, MikulanJ, LinP, LetterioJJ and DennisJE. (2010). Targeting improves MSC treatment of inflammatory bowel disease. Mol Ther, 18:1365–1372.
10.
AugelloA, TassoR, NegriniSM, CanceddaR and PennesiG. (2007). Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum, 56:1175–1186.
11.
GuptaN, SuX, PopovB, LeeJW, SerikovV and MatthayMA. (2007). Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol, 179:1855–1863.
12.
BaronF and StorbR. (2012). Mesenchymal stromal cells: a new tool against graft-versus-host disease?. Biol Blood Marrow Transplant, 18:822–840.
13.
BruckF, BelleL, LechanteurC, de LevalL, HannonM, DuboisS, CastermansE, Humblet-BaronS, RahmouniS, et al. (2013). Impact of bone marrow-derived mesenchymal stromal cells on experimental xenogeneic graft-versus-host disease. Cytotherapy, 15:267–279.
14.
GordonD, PavlovskaG, GloverCP, UneyJB, WraithD and ScoldingNJ. (2008). Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration. Neurosci Lett, 448:71–73.
15.
ZhouK, ZhangH, JinO, FengX, HouY and SunL. (2009). Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL/lpr mice. Cell Mol Immunol, 5:417–424.
16.
LiuY, MuR, WangS, LongL, LiuX, LiR, SunJ, GuoJ, ZhangX, et al. (2010). Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Arthritis Res Ther, 12:R210.
17.
GonzalezMA, Gonzalez-ReyE, RicoL, BuscherD and DelgadoM. (2009). Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology, 136:978–989.
18.
ShiY, SuJ, RobertsAI, ShouP, RabsonAB and RenG. (2012). How mesenchymal stem cells interact with tissue immune responses. Trends Immunol, 33:136–143.
19.
MaS, XieN, LiW, YuanB, ShiY and WangY. (2014). Immunobiology of mesenchymal stem cells. Cell Death Differ, 21:216–225.
20.
HoogduijnMJ, PoppF, VerbeekR, MasoodiM, NicolaouA, BaanC and DahlkeMH. (2010). The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int Immunopharmacol, 10:1496–1500.
21.
SuJ, ChenX, HuangY, LiW, LiJ, CaoK, CaoG, ZhangL, LiF, et al. (2014). Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell-mediated immunosuppression in mammalian species. Cell Death Differ, 21:388–396.
22.
LingW, ZhangJ, YuanZ, RenG, ZhangL, ChenX, RabsonAB, RobertsAI, WangY and ShiY. (2014). Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment. Cancer Res, 74:1576–1587.
23.
AggarwalS and PittengerMF. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105:1815–1822.
24.
ChenK, WangD, DuWT, HanZB, RenH, ChiY, YangSG, ZhuD, BayardF and HanZC. (2010). Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism. Clin Immunol, 135:448–458.
25.
HegyiB, KudlikG, MonostoriE and UherF. (2012). Activated T-cells and pro-inflammatory cytokines differentially regulate prostaglandin E2 secretion by mesenchymal stem cells. Biochem Biophys Res Commun, 419:215–220.
26.
XuC, YuP, HanX, DuL, GanJ, WangY and ShiY. (2013). TGF-beta promotes immune responses in the presence of mesenchymal stem cells. J Immunol, 192:103–109.
27.
OrtizLA, DutreilM, FattmanC, PandeyAC, TorresG, GoK and PhinneyDG. (2007). Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A, 104:11002–11007.
28.
Juge-AubryCE, SommE, ChicheporticheR, BurgerD, PerninA, Cuénod-PittetB, QuinodozP, GiustiV, DayerJM and MeierCA. (2004). Regulatory effects of interleukin (IL)-1, interferon-beta, and IL-4 on the production of IL-1 receptor antagonist by human adipose tissue. J Clin Endocrinol Metab, 89:2652–2658.
29.
RizzoR, CampioniD, StignaniM, MelchiorriL, BagnaraGP, BonsiL, AlvianoF, LanzoniG, MorettiS, et al. (2008). A functional role for soluble HLA-G antigens in immune modulation mediated by mesenchymal stromal cells. Cytotherapy, 10:364–375.
30.
SelmaniZ, NajiA, ZidiI, FavierB, GaiffeE, ObertL, BorgC, SaasP, TiberghienP, et al. (2008). Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells, 26:212–222.
31.
WangWB, YenML, LiuKJ, HsuPJ, LinMH, ChenPM, SudhirPR, ChenCH, ChenCH, SytwuHK and YenBL. (2015). Interleukin-25 mediates transcriptional control of PD-L1 via STAT3 in multipotent human mesenchymal stromal cells (hMSCs) to suppress Th17 responses. Stem Cell Reports, 5:392–404.
32.
GuYZ, XueQ, ChenYJ, YuGH, QingMD, ShenY, WangMY, ShiQ and ZhangXG. (2013). Different roles of PD-L1 and FasL in immunomodulation mediated by human placenta-derived mesenchymal stem cells. Hum Immunol, 74:267–276.
33.
RenG, ZhangL, ZhaoX, XuG, ZhangY, RobertsAI, ZhaoRC and ShiY. (2008). Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell, 2:141–150.
34.
RenG, SuJ, ZhangL, ZhaoX, LingW, L'HuillieA, ZhangJ, LuY, RobertsAI, et al. (2009). Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells, 27:1954–1962.
35.
ShengH, WangY, JinY, ZhangQ, ZhangY, WangL, ShenB, YinS, LiuW, CuiL and LiN. (2008). A critical role of IFN[gamma] in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res, 18:846–857.
36.
KramperaM, CosmiL, AngeliR, PasiniA, LiottaF, AndreiniA, SantarlasciV, MazzinghiB, PizzoloG, et al. (2006). Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells, 24:386–398.
37.
TomchuckSL, ZwezdarykKJ, CoffeltSB, WatermanRS, DankaES and ScandurroAB. (2008). Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells, 26:99–107.
38.
JungYJ, JuSY, YooES, ChoS, ChoKA, WooSY, SeohJY, ParkJW, HanHS and RyuKH. (2007). MSC-DC interactions: MSC inhibit maturation and migration of BM-derived DC. Cytotherapy, 9:451–458.
39.
EnglishK, BarryFP and MahonBP. (2007). Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation. Immunol Lett, 115:50–58.
40.
NautaAJ, KruisselbrinkAB, LurvinkE, WillemzeR and FibbeWE. (2006). Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol, 177:2080–2087.
41.
ZeiraO, AsiagN, ArallaM, GhezziE, PettinariL, MartinelliL, ZahirpourD, DumasMP, LupiD, et al. (2015). Adult autologous mesenchymal stem cells for the treatment of suspected non-infectious inflammatory diseases of the canine central nervous system: safety, feasibility and preliminary clinical findings. J Neuroinflammation, 12:181.
42.
VillatoroAJ, FernandezV, ClarosS, Rico-LlanosGA, BecerraJ and AndradesJA. (2015). Use of adipose-derived mesenchymal stem cells in keratoconjunctivitis sicca in a canine model. Biomed Res Int, 2015:527926.
43.
FerrerL, KimbrelEA, LamA, FalkEB, ZeweC, JuopperiT, LanzaR and HoffmanA. (2016). Treatment of perianal fistulas with human embryonic stem cell-derived mesenchymal stem cells: a canine model of human fistulizing Crohn's disease. Regen Med, 11:33–43.
44.
BlackLL, GaynorJ, AdamsC, DhupaS, SamsAE, TaylorR, HarmanS, GingerichDA and HarmanR. (2008). Effect of intraarticular injection of autologous adipose-derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs. Vet Ther, 9:192–200.
45.
CuervoB, RubioM, SopenaJ, DominguezJM, VilarJ, MoralesM, CugatR and CarrilloJM. (2014). Hip osteoarthritis in dogs: a randomized study using mesenchymal stem cells from adipose tissue and plasma rich in growth factors. Int J Mol Sci, 15:13437–13460.
46.
GuercioA, Di MarcoP, CasellaS, CannellaV, RussottoL, PurpariG, Di BellaS and PiccioneG. (2012). Production of canine mesenchymal stem cells from adipose tissue and their application in dogs with chronic osteoarthritis of the humeroradial joints. Cell Biol Int, 36:189–194.
47.
HiyamaA, MochidaJ, IwashinaT, OmiH, WatanabeT, SeriganoK, TamuraF and SakaiD. (2008). Transplantation of mesenchymal stem cells in a canine disc degeneration model. J Orthop Res, 26:589–600.
48.
YunS, KuSK and KwonYS. (2016). Adipose-derived mesenchymal stem cells and platelet-rich plasma synergistically ameliorate the surgical-induced osteoarthritis in Beagle dogs. J Orthop Surg Res, 11:9.
49.
WhitworthDJ and BanksTA. (2014). Stem cell therapies for treating osteoarthritis: prescient or premature?. Vet J, 202:416–424.
MielcarekM, StorbR, GeorgesGE, GolubevL, NikitineA, HwangB, NashRA and Torok-StorbB. (2011). Mesenchymal stromal cells fail to prevent acute graft-versus-host disease and graft rejection after dog leukocyte antigen-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant, 17:214–225.
52.
KimH-S, KimK-H, KimS-H, KimY-S, KooK-T, KimT-I, SeolY-J, KuY, RhyuI-C, ChungC-P and LeeY-M. (2010). Immunomodulatory effect of canine periodontal ligament stem cells on allogenic and xenogenic peripheral blood mononuclear cells. J Periodontal Implant Sci, 40:265–270.
53.
ClarkKC, KolA, ShahbenderianS, GranickJL, WalkerNJ and BorjessonDL. (2016). Canine and equine mesenchymal stem cells grown in serum free media have altered immunophenotype. Stem Cell Rev, 12:245–256.
54.
LeeWS, SuzukiY, GravesSS, IwataM, VenkataramanGM, MielcarekM, PetersonLJ, IkeharaS, Torok-StorbB and StorbR. (2011). Canine bone marrow derived mesenchymal stromal cells suppress allo-reactive lymphocyte proliferation in vitro but fail to enhance engraftment in canine bone marrow transplantation. Biol Blood Marrow Transplant, 17:465–475.
55.
WhitworthDJ, FrithJE, FrithTJ, OvchinnikovDA, Cooper-WhiteJJ and WolvetangEJ. (2014). Derivation of mesenchymal stromal cells from canine induced pluripotent stem cells by inhibition of the TGFbeta/activin signaling pathway. Stem Cells Dev, 23:3021–3033.
56.
JiangY, JahagirdarBN, ReinhardtRL, SchwartzRE, KeeneCD, Ortiz-GonzalezXR, ReyesM, LenvikT, LundT, et al. (2002). Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 418:41–49.
57.
WangX and DaiJ. (2010). Concise review: isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem Cells, 28:885–893.
58.
GlennJD and WhartenbyKA. (2014). Mesenchymal stem cells: emerging mechanisms of immunomodulation and therapy. World J Stem Cells, 6:526–539.
59.
KyurkchievD, BochevI, Ivanova-TodorovaE, MourdjevaM, OreshkovaT, BelemezovaK and KyurkchievS. (2014). Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells, 6:552–570.
HoffmanAM and DowSW. (2016). Concise review: stem cell trials using companion animal disease models. Stem Cells, 34:1709–1729.
65.
GaoF, ChiuSM, MotanDA, ZhangZ, ChenL, JiHL, TseHF, FuQL and LianQ. (2015). Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis, 7:e2062.
66.
KhatriM, O'BrienTD, ChatthaKS and SaifLJ. (2015). Porcine lung mesenchymal stromal cells possess differentiation and immunoregulatory properties. Stem Cell Res Ther, 6:222.
67.
YangS-H, ParkM-J, YoonI-H, KimS-Y, HongS-H, ShinJ-Y, NamH-Y, KimY-H, KimB and ParkC-G. (2009). Soluble mediators from mesenchymal stem cells suppress T cell proliferation by inducing IL-10. Exp Mol Med, 41:315–324.
68.
KuçiZ, SeiberthJ, Latifi-PupovciH, WehnerS, SteinS, GrezM, BönigH, KöhlU, KlingebielT, BaderP and KuçiS. (2013). Clonal analysis of multipotent stromal cells derived from CD271(+) bone marrow mononuclear cells: functional heterogeneity and different mechanisms of allosuppression. Haematologica, 98:1609–1616.
69.
ElmanJS, LiM, WangF, GimbleJM and ParekkadanB. (2014). A comparison of adipose and bone marrow-derived mesenchymal stromal cell secreted factors in the treatment of systemic inflammation. J Inflamm (Lond), 11:1.
70.
LiaoHT and ChenCT. (2014). Osteogenic potential: comparison between bone marrow and adipose-derived mesenchymal stem cells. World J Stem Cells, 6:288–295.
71.
SzepesM, BenkoZ, CselenyakA, KompischKM, SchumacherU, LaczaZ and KissL. (2013). Comparison of the direct effects of human adipose- and bone-marrow-derived stem cells on postischemic cardiomyoblasts in an in vitro simulated ischemia-reperfusion model. Stem Cells Int, 2013:178346.
72.
RasmussenJG, FrobertO, Holst-HansenC, KastrupJ, BaandrupU, ZacharV, FinkT and SimonsenU. (2014). Comparison of human adipose-derived stem cells and bone marrow-derived stem cells in a myocardial infarction model. Cell Transplant, 23:195–206.
73.
OckSA, Baregundi SubbaraoR, LeeYM, LeeJH, JeonRH, LeeSL, ParkJK, HwangSC and RhoGJ. (2016). Comparison of immunomodulation properties of porcine mesenchymal stromal/stem cells derived from the bone marrow, adipose tissue, and dermal skin tissue. Stem Cells Int, 2016:9581350.
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