Restricted accessResearch articleFirst published online 2016-10
Mesenchymal Stem Cells Derived from Human Bone Marrow and Adipose Tissue Maintain Their Immunosuppressive Properties After Chondrogenic Differentiation: Role of HLA-G
Mesenchymal stem cells (MSC) have emerged as alternative sources of stem cells for regenerative medicine because of their multipotency and strong immune-regulatory properties. Also, human leukocyte antigen G (HLA-G) is an important mediator of MSC-mediated immunomodulation. However, it is unclear whether MSC retain their immune-privileged potential after differentiation. As promising candidates for cartilage tissue engineering, the immunogenic and immunomodulatory properties of chondro-differentiated MSC (chondro-MSC) require in-depth exploration. In the present study, we used the alginate/hyaluronic acid (Alg/HA) hydrogel scaffold and induced both bone marrow- and adipose tissue-derived MSC into chondrocytes in three-dimensional condition. Then, MSC before and after chondrocyte differentiation were treated or not with interferon γ and tumor necrosis factor α mimicking inflammatory conditions and were compared side by side using flow cytometry, mixed lymphocyte reaction, and immunostaining assays. Results showed that chondro-MSC were hypoimmunogenic and could exert immunosuppression on HLA-mismatched peripheral blood mononuclear cells as well as undifferentiated MSC did. This alloproliferation inhibition mediated by MSC or chondro-MSC was dose dependent. Meanwhile, chondro-MSC exerted inhibition on natural killer cell-mediated cytolysis. Also, we showed that HLA-G expression was upregulated in chondro-MSC under hypoxia context and could be boosted in allogenic settings. Besides, the Alg/HA hydrogel scaffold was hypoimmunogenic and its addition for supporting MSC chondrocyte differentiation did not modify the immune properties of MSC. Finally, considering their chondro-regenerative potential and their retained immunosuppressive capacity, MSC constitute promising allogenic sources of stem cells for cartilage repair.
Get full access to this article
View all access options for this article.
References
1.
VilquinJT and RossetP. (2006). Mesenchymal stem cells in bone and cartilage repair: current status. Regen Med, 1:589–604.
2.
RingeJ, HauplT and SittingerM. (2007). Future of tissue engineering in rheumatic diseases. Expert Opin Biol Ther, 7:283–287.
3.
BrittbergM, LindahlA, NilssonA, OhlssonC, IsakssonO and PetersonL. (1994). Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med, 331:889–895.
4.
BuckleyCT, VinardellT, ThorpeSD, HaughMG, JonesE, McGonagleD and KellyDJ. (2010). Functional properties of cartilaginous tissues engineered from infrapatellar fat pad-derived mesenchymal stem cells. J Biomech, 43:920–926.
5.
UccelliA, PistoiaV and MorettaL. (2007). Mesenchymal stem cells: a new strategy for immunosuppression?. Trends Immunol, 28:219–226.
6.
UccelliA, MorettaL and PistoiaV. (2008). Mesenchymal stem cells in health and disease. Nat Rev Immunol, 8:726–736.
7.
ShiY, HuG, SuJ, LiW, ChenQ, ShouP, XuC, ChenX, HuangY, et al. (2010). Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res, 20:510–518.
8.
Le BlancK, RasmussonI, SundbergB, GotherstromC, HassanM, UzunelM and RingdenO. (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet, 363:1439–1441.
9.
AugelloA, TassoR, NegriniSM, AmateisA, IndiveriF, CanceddaR and PennesiG. (2005). Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol, 35:1482–1490.
10.
SatoK, OzakiK, OhI, MeguroA, HatanakaK, NagaiT, MuroiK and OzawaK. (2007). Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood, 109:228–234.
11.
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.
12.
Di NicolaM, Carlo-StellaC, MagniM, MilanesiM, LongoniPD, MatteucciP, GrisantiS and GianniM. (2002). Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 99:3838–3843.
13.
AggarwalS and PittengerMF. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105:1815–1822.
14.
ChabannesD, HillM, MerieauE, RossignolJ, BrionR, SoulillouJP, AnegonI and CuturiMC. (2007). A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood, 110:3691–3694.
15.
DjouadF, CharbonnierLM, BouffiC, Louis-PlenceP, BonyC, ApparaillyF, CantosC, JorgensenC and NoelD. (2007). Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells, 25:2025–2032.
16.
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.
17.
NajiA, Rouas-FreissN, DurrbachA, CarosellaED, SensebeL and DeschaseauxF. (2013). Concise review: combining human leukocyte antigen G and mesenchymal stem cells for immunosuppressant biotherapy. Stem Cells, 31:2296–2303.
18.
HuangXP, SunZ, MiyagiY, McDonald KinkaidH, ZhangL, WeiselRD and LiRK. (2010). Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation, 122:2419–2429.
19.
ZhaoQ, RenH, LiX, ChenZ, ZhangX, GongW, LiuY, PangT and HanZC. (2009). Differentiation of human umbilical cord mesenchymal stromal cells into low immunogenic hepatocyte-like cells. Cytotherapy, 11:414–426.
20.
MontespanF, DeschaseauxF, SensebeL, CarosellaED and Rouas-FreissN. (2014). Osteodifferentiated mesenchymal stem cells from bone marrow and adipose tissue express HLA-G and display immunomodulatory properties in HLA-mismatched settings: implications in bone repair therapy. J Immunol Res, 2014:230346.
21.
Tritz-SchiaviJ, CharifN, HenrionnetC, de IslaN, BensoussanD, MagdalouJ, Benkirane-JesselN, StoltzJF and HuselsteinC. (2010). Original approach for cartilage tissue engineering with mesenchymal stem cells. Biomed Mater Eng, 20:167–174.
22.
TibbittMW and AnsethKS. (2009). Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnol Bioeng, 103:655–663.
23.
PeltzerJ, MontespanF, ThepenierC, BoutinL, UzanG, Rouas-FreissN and LatailladeJJ. (2015). Heterogeneous functions of perinatal mesenchymal stromal cells require a preselection before their banking for clinical use. Stem Cells Dev, 24:329–344.
24.
ReppelL, SchiaviJ, CharifN, LegerL, YuH, PinzanoA, HenrionnetC, StoltzJF, BensoussanD and HuselsteinC. (2015). Chondrogenic induction of mesenchymal stromal/stem cells from Wharton's jelly embedded in alginate hydrogel and without added growth factor: an alternative stem cell source for cartilage tissue engineering. Stem Cell Res Ther, 6:260.
25.
MoraisDS, RodriguesMA, SilvaTI, LopesMA, SantosM, SantosJD and BotelhoCM. (2013). Development and characterization of novel alginate-based hydrogels as vehicles for bone substitutes. Carbohydr Polym, 95:134–142.
26.
DahlmannJ, KrauseA, MollerL, KensahG, MowesM, DiekmannA, MartinU, KirschningA, GruhI and DragerG. (2013). Fully defined in situ cross-linkable alginate and hyaluronic acid hydrogels for myocardial tissue engineering. Biomaterials, 34:940–951.
BahriR, NajiA, MenierC, CharpentierB, CarosellaED, Rouas-FreissN and DurrbachA. (2009). Dendritic cells secrete the immunosuppressive HLA-G molecule upon CTLA4-Ig treatment: implication in human renal transplant acceptance. J Immunol, 183:7054–7062.
29.
ChenX, McClurgA, ZhouGQ, McCaigueM, ArmstrongMA and LiG. (2007). Chondrogenic differentiation alters the immunosuppressive property of bone marrow-derived mesenchymal stem cells, and the effect is partially due to the upregulated expression of B7 molecules. Stem Cells, 25:364–370.
30.
TechnauA, FroelichK, HagenR and KleinsasserN. (2011). Adipose tissue-derived stem cells show both immunogenic and immunosuppressive properties after chondrogenic differentiation. Cytotherapy, 13:310–317.
31.
Rouas-FreissN, MarchalRE, KirszenbaumM, DaussetJ and CarosellaED. (1997). The alpha1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: is HLA-G the public ligand for natural killer cell inhibitory receptors?. Proc Natl Acad Sci U S A, 94:5249–5254.
32.
PaulP, Rouas-FreissN, Khalil-DaherI, MoreauP, RiteauB, Le GalFA, AvrilMF, DaussetJ, GuilletJG and CarosellaED. (1998). HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci U S A, 95:4510–4515.
33.
DingDC, ChouHL, ChangYH, HungWT, LiuHW and ChuTY. (2015). Characterization of HLA-G and related immunosuppressive effects in human umbilical cord stroma derived stem cells. Cell Transplant, 25:217–228.
34.
YangZX, HanZB, JiYR, WangYW, LiangL, ChiY, YangSG, LiLN, LuoWF, et al. (2013). CD106 identifies a subpopulation of mesenchymal stem cells with unique immunomodulatory properties. PLoS One, 8:e59354.
35.
ReppelL, MargossianT, YaghiL, MoreauP, MercierN, LegerL, HupontS, StoltzJF, BensoussanD and HuselsteinC. (2014). Hypoxic culture conditions for mesenchymal stromal/stem cells from Wharton's jelly: a critical parameter to consider in a therapeutic context. Curr Stem Cell Res Ther, 9:306–318.
36.
RizzoR, LanzoniG, StignaniM, CampioniD, AlvianoF, RicciF, TazzariPL, MelchiorriL, ScalinciSZ, et al. (2011). A simple method for identifying bone marrow mesenchymal stromal cells with a high immunosuppressive potential. Cytotherapy, 13:523–527.
37.
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.
38.
HuangS, XuL, SunY, ZhangY and LiG. (2015). The fate of systemically administrated allogeneic mesenchymal stem cells in mouse femoral fracture healing. Stem Cell Res Ther, 6:206.
39.
van VelthovenCT, KavelaarsA, van BelF and HeijnenCJ. (2011). Mesenchymal stem cell transplantation changes the gene expression profile of the neonatal ischemic brain. Brain Behav Immun, 25:1342–1348.
40.
LeeJA, KimBI, JoCH, ChoiCW, KimEK, KimHS, YoonKS and ChoiJH. (2010). Mesenchymal stem-cell transplantation for hypoxic-ischemic brain injury in neonatal rat model. Pediatr Res, 67:42–46.
41.
YasuharaT, HaraK, MakiM, MaysRW, DeansRJ, HessDC, CarrollJE and BorlonganCV. (2008). Intravenous grafts recapitulate the neurorestoration afforded by intracerebrally delivered multipotent adult progenitor cells in neonatal hypoxic-ischemic rats. J Cereb Blood Flow Metab, 28:1804–1810.
42.
van VelthovenCT, KavelaarsA, van BelF and HeijnenCJ. (2010). Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage. Pediatr Res, 68:419–422.
