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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.

Montespan F, Deschaseaux F, Sensébé L, Carosella ED, Rouas-Freiss N - J Immunol Res (2014)

Bottom Line: Both MSCs and osteodifferentiated MSCs are hypoimmunogenic and exert immunomodulatory properties in HLA-mismatched settings as they suppress T cell alloproliferation in mixed lymphocyte reactions.Finally, addition of biomaterials that stimulate bone tissue formation did not modify MSC immune properties.As MSCs combine both abilities of osteoregeneration and immunomodulation, they may be considered as allogenic sources for the treatment of bone defects.

View Article: PubMed Central - PubMed

Affiliation: CEA, Institut des Maladies Emergentes et des Therapies Innovantes (IMETI), Service de Recherche en Hemato-Immunologie (SRHI), Hopital Saint-Louis, IUH, 1 avenue Claude Vellefaux, 75010 Paris, France ; Universite Paris Diderot, Sorbonne Paris Cité, IUH, Hopital Saint-Louis, UMR_E5, IUH, 1, avenue Claude Vellefaux, 75010 Paris, France.

ABSTRACT
Mesenchymal stem cells (MSCs) are multipotent cells that can be obtained from several sources such as bone marrow and adipose tissue. Depending on the culture conditions, they can differentiate into osteoblasts, chondroblasts, adipocytes, or neurons. In this regard, they constitute promising candidates for cell-based therapy aimed at repairing damaged tissues. In addition, MSCs display immunomodulatory properties through the expression of soluble factors including HLA-G. We here analyse both immunogenicity and immunosuppressive capacity of MSCs derived from bone marrow and adipose tissue before and after osteodifferentiation. Results show that HLA-G expression is maintained after osteodifferentiation and can be boosted in inflammatory conditions mimicked by the addition of IFN-γ and TNF-α. Both MSCs and osteodifferentiated MSCs are hypoimmunogenic and exert immunomodulatory properties in HLA-mismatched settings as they suppress T cell alloproliferation in mixed lymphocyte reactions. Finally, addition of biomaterials that stimulate bone tissue formation did not modify MSC immune properties. As MSCs combine both abilities of osteoregeneration and immunomodulation, they may be considered as allogenic sources for the treatment of bone defects.

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Both BM- andAT-derived MSCs when combined to MBCP biomaterial keep their immunosuppressive properties. PBMC from healthy individuals were used as responder cells towards irradiated LCL* used as stimulating cells in presence of either BM-derived MSCs (MSC-BM) or AT-derived MSCs (MSC-AT) that were pretreated with IFNγ and TNFα (IFNγ/TNFα) or not and used as third-party cells at various responder : stimulator : MSC ratios. MSCs were combined to MBCP biomaterial (MBCP) or not (No MBCP). Results are given as mean percentage of alloproliferation inhibition ± s.e.m. when compared to PBMC+LCL* using PBMC from 3 distinct healthy donors.
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fig7: Both BM- andAT-derived MSCs when combined to MBCP biomaterial keep their immunosuppressive properties. PBMC from healthy individuals were used as responder cells towards irradiated LCL* used as stimulating cells in presence of either BM-derived MSCs (MSC-BM) or AT-derived MSCs (MSC-AT) that were pretreated with IFNγ and TNFα (IFNγ/TNFα) or not and used as third-party cells at various responder : stimulator : MSC ratios. MSCs were combined to MBCP biomaterial (MBCP) or not (No MBCP). Results are given as mean percentage of alloproliferation inhibition ± s.e.m. when compared to PBMC+LCL* using PBMC from 3 distinct healthy donors.

Mentions: Then, we investigated the immunomodulatory properties of MSCs as third-party cells in MLR. Results showed that both BM-derived and AT-derived MSCs display immunosuppressive properties in a dose-response manner (Figure 6). It is of note that (i) AT-derived MSCs are more potent at low doses compared to BM-derived MSCs (P < 0.05) (Figures 6(a) and 6(b)) and (ii) licensing with cytokines reduces significantly the immunosuppressive properties of AT-derived MSCs (P < 0.05) (Figure 6(b)). When combined to biomaterial (MBCP), both BM-derived and AT-derived MSCs still exert immunosuppressive properties as they greatly inhibit T cell alloproliferation with or without being seeded with MBCP (Figure 7). Although not statistically significant, addition of MBCP reduces the immunomodulatory properties of BM-derived MSCs at high responder: stimulator: MSC ratios. This could be due to steric hindrance when high numbers of cells are used. Indeed, such MBCP effect is no longer observed at low ratios (Figure 7). Also, both BM-derived and AT-derived MSCs when committed to preosteoblastic MSCs inhibit T cell alloproliferation and remain thus able to induce a tolerogenic microenvironment (Figure 8). Licensing with IFN-γ and TNF-α did not modify such MSC-derived immunosuppression (Figures 7 and 8). It is of note that once osteodifferentiated AT-derived MSCs are more potent at low doses compared to BM-derived MSCs as they display higher immunosuppressive effects (P < 0.05) (Figure 8). Such higher immunomodulatory capacity of adipose tissue-derived multipotent stromal cells compared to their bone marrow-derived counterparts has been previously reported [19].


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.

Montespan F, Deschaseaux F, Sensébé L, Carosella ED, Rouas-Freiss N - J Immunol Res (2014)

Both BM- andAT-derived MSCs when combined to MBCP biomaterial keep their immunosuppressive properties. PBMC from healthy individuals were used as responder cells towards irradiated LCL* used as stimulating cells in presence of either BM-derived MSCs (MSC-BM) or AT-derived MSCs (MSC-AT) that were pretreated with IFNγ and TNFα (IFNγ/TNFα) or not and used as third-party cells at various responder : stimulator : MSC ratios. MSCs were combined to MBCP biomaterial (MBCP) or not (No MBCP). Results are given as mean percentage of alloproliferation inhibition ± s.e.m. when compared to PBMC+LCL* using PBMC from 3 distinct healthy donors.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4022112&req=5

fig7: Both BM- andAT-derived MSCs when combined to MBCP biomaterial keep their immunosuppressive properties. PBMC from healthy individuals were used as responder cells towards irradiated LCL* used as stimulating cells in presence of either BM-derived MSCs (MSC-BM) or AT-derived MSCs (MSC-AT) that were pretreated with IFNγ and TNFα (IFNγ/TNFα) or not and used as third-party cells at various responder : stimulator : MSC ratios. MSCs were combined to MBCP biomaterial (MBCP) or not (No MBCP). Results are given as mean percentage of alloproliferation inhibition ± s.e.m. when compared to PBMC+LCL* using PBMC from 3 distinct healthy donors.
Mentions: Then, we investigated the immunomodulatory properties of MSCs as third-party cells in MLR. Results showed that both BM-derived and AT-derived MSCs display immunosuppressive properties in a dose-response manner (Figure 6). It is of note that (i) AT-derived MSCs are more potent at low doses compared to BM-derived MSCs (P < 0.05) (Figures 6(a) and 6(b)) and (ii) licensing with cytokines reduces significantly the immunosuppressive properties of AT-derived MSCs (P < 0.05) (Figure 6(b)). When combined to biomaterial (MBCP), both BM-derived and AT-derived MSCs still exert immunosuppressive properties as they greatly inhibit T cell alloproliferation with or without being seeded with MBCP (Figure 7). Although not statistically significant, addition of MBCP reduces the immunomodulatory properties of BM-derived MSCs at high responder: stimulator: MSC ratios. This could be due to steric hindrance when high numbers of cells are used. Indeed, such MBCP effect is no longer observed at low ratios (Figure 7). Also, both BM-derived and AT-derived MSCs when committed to preosteoblastic MSCs inhibit T cell alloproliferation and remain thus able to induce a tolerogenic microenvironment (Figure 8). Licensing with IFN-γ and TNF-α did not modify such MSC-derived immunosuppression (Figures 7 and 8). It is of note that once osteodifferentiated AT-derived MSCs are more potent at low doses compared to BM-derived MSCs as they display higher immunosuppressive effects (P < 0.05) (Figure 8). Such higher immunomodulatory capacity of adipose tissue-derived multipotent stromal cells compared to their bone marrow-derived counterparts has been previously reported [19].

Bottom Line: Both MSCs and osteodifferentiated MSCs are hypoimmunogenic and exert immunomodulatory properties in HLA-mismatched settings as they suppress T cell alloproliferation in mixed lymphocyte reactions.Finally, addition of biomaterials that stimulate bone tissue formation did not modify MSC immune properties.As MSCs combine both abilities of osteoregeneration and immunomodulation, they may be considered as allogenic sources for the treatment of bone defects.

View Article: PubMed Central - PubMed

Affiliation: CEA, Institut des Maladies Emergentes et des Therapies Innovantes (IMETI), Service de Recherche en Hemato-Immunologie (SRHI), Hopital Saint-Louis, IUH, 1 avenue Claude Vellefaux, 75010 Paris, France ; Universite Paris Diderot, Sorbonne Paris Cité, IUH, Hopital Saint-Louis, UMR_E5, IUH, 1, avenue Claude Vellefaux, 75010 Paris, France.

ABSTRACT
Mesenchymal stem cells (MSCs) are multipotent cells that can be obtained from several sources such as bone marrow and adipose tissue. Depending on the culture conditions, they can differentiate into osteoblasts, chondroblasts, adipocytes, or neurons. In this regard, they constitute promising candidates for cell-based therapy aimed at repairing damaged tissues. In addition, MSCs display immunomodulatory properties through the expression of soluble factors including HLA-G. We here analyse both immunogenicity and immunosuppressive capacity of MSCs derived from bone marrow and adipose tissue before and after osteodifferentiation. Results show that HLA-G expression is maintained after osteodifferentiation and can be boosted in inflammatory conditions mimicked by the addition of IFN-γ and TNF-α. Both MSCs and osteodifferentiated MSCs are hypoimmunogenic and exert immunomodulatory properties in HLA-mismatched settings as they suppress T cell alloproliferation in mixed lymphocyte reactions. Finally, addition of biomaterials that stimulate bone tissue formation did not modify MSC immune properties. As MSCs combine both abilities of osteoregeneration and immunomodulation, they may be considered as allogenic sources for the treatment of bone defects.

Show MeSH