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. 2013 Jun;2(6):455-63.
doi: 10.5966/sctm.2012-0184. Epub 2013 May 21.

Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts

Sara M Melief  1 , Jaap Jan Zwaginga, Willem E Fibbe, Helene Roelofs
Affiliations

Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts

Sara M Melief et al. Stem Cells Transl Med. 2013 Jun.

Abstract

Adipose tissue-derived multipotent stromal cells (AT-MSCs) are studied as an alternative to bone marrow-derived multipotent stromal cells (BM-MSCs) for immunomodulatory treatment. In this study, we systematically compared the immunomodulatory capacities of BM-MSCs and AT-MSCs derived from age-matched donors. We found that BM-MSCs and AT-MSCs share a similar immunophenotype and capacity for in vitro multilineage differentiation. BM-MSCs and AT-MSCs showed comparable immunomodulatory effects as they were both able to suppress proliferation of stimulated peripheral blood mononuclear cells and to inhibit differentiation of monocyte-derived immature dendritic cells. However, at equal cell numbers, the AT-MSCs showed more potent immunomodulatory effects in both assays as compared with BM-MSCs. Moreover, AT-MSCs showed a higher level of secretion of cytokines that have been implicated in the immunomodulatory modes of action of multipotent stromal cells, such as interleukin-6 and transforming growth factor-β1. This is correlated with higher metabolic activity of AT-MSCs compared with BM-MSCs. We conclude that the immunomodulatory capacities of BM-MSCs and AT-MSCs are similar, but that differences in cytokine secretion cause AT-MSCs to have more potent immunomodulatory effects than BM-MSCs. Therefore, lower numbers of AT-MSCs evoke the same level of immunomodulation. These data indicate that AT-MSCs can be considered as a good alternative to BM-MSCs for immunomodulatory therapy.

Keywords: Adult human bone marrow; Bone marrow; Bone marrow stromal cells; Cellular therapy; Immunosuppression; Marrow stromal stem cells; Mesenchymal stem cells.

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Figures

Figure 1.
Figure 1.
Bone marrow-derived multipotent stromal cells (BM-MSCs) and adipose tissue-derived multipotent stromal cells (AT-MSCs) show the same immunophenotype, except for CD34 expression. (A, B): Representative histograms of BM-MSC (A) and AT-MSC (B) fluorescence-activated cell sorting (FACS) analysis. All AT-MSC donors showed a CD34+ population. Gray histograms are isotype control. (C): Cumulative data of FACS analysis of BM-MSCs and AT-MSCs for several surface markers. The expression of CD34 was significantly higher on AT-MSCs compared with BM-MSCs (data are means from four BM-MSC and five AT-MSC donors; statistical analysis was performed using a two-way analysis of variance; *, p < .05; **, p < .01; ***, p < .001). Abbreviations: AT, adipose tissue-derived multipotent stromal cells; BM, bone marrow-derived multipotent stromal cells; HLA, human leukocyte antigen; pos, positive.
Figure 2.
Figure 2.
BM-MSCs and AT-MSCs both differentiate toward the osteogenic and adipogenic lineages. Confluent cultures of BM-MSCs (A–C) and AT-MSCs (D–F) were maintained in osteogenic differentiation medium (A, D), adipogenic differentiation medium (B, E), or control medium (C, F). After 3 weeks of culture in differentiation medium, both BM-MSCs and AT-MSCs were positive for alkaline phosphatase activity (A, D) and lipid droplets were formed (B, E). Control cultures in proliferation medium did not show alkaline phosphatase activity or the formation of lipid droplets. Multipotent stromal cell populations from six BM-MSC donors and from eight AT-MSC donors were tested for their differentiation capacity; representative pictures are shown for BM-MSCs and AT-MSCs. Scale bar = 50 μm. Abbreviations: Adipo, adipogenic; AT-MSC, adipose tissue-derived multipotent stromal cells; BM-MSC, bone marrow-derived multipotent stromal cells; Osteo, osteogenic.
Figure 3.
Figure 3.
AT-MSCs are more potent in suppressing PBMC proliferation compared with BM-MSCs. (A): MSCs suppressed PBMC proliferation in a dose-dependent fashion. AT-MSCs showed a significantly stronger suppression of proliferation at MSC:PBMC ratios of 1:100, 1:32, and 1:10 (two separate experiments; n = 9 for AT-MSCs, n = 8 for BM-MSCs). (B): From one experiment, culture supernatants of PBMC proliferation in the presence and absence of MSCs were assayed for cytokine concentrations at day 5 of coculture (n = 3 for both groups). Statistical analysis was performed using Student's t test (data are mean ± SEM; * indicates compared with control: *, p < .05; **, p < .01; ***, p < .001; # indicates AT-MSCs compared with BM-MSCs: #, p < .05; ##, p < .01). (C): After IFN-γ stimulation of MSCs, both BM-MSCs and AT-MSCs showed IDO mRNA upregulation, with an optimum at 8 hours. IDO mRNA expression is shown relative to β-actin mRNA expression. Statistical analysis was performed using Student's t test (n = 3 for both groups). Abbreviations: AT MSC, adipose tissue-derived multipotent stromal cells; BM MSC, bone marrow-derived multipotent stromal cells; IDO, indoleamine 2,3-dioxygenase; MSC, multipotent stromal cells; PBMC, peripheral blood mononuclear cells.
Figure 4.
Figure 4.
AT-MSCs are more potent inhibitors of monocyte differentiation than BM-MSCs. (A): Representative dot plots of monocyte differentiation toward immature dendritic cells in the absence and presence of BM-MSCs and AT-MSCs (MSC:monocyte ratio of 1:10). (B): Cumulative data of CD1a and CD14 expression on differentiated monocytes. Data are means from three different BM-MSCs and three different AT-MSCs (MSC:monocyte ratio of 1:10); statistical analysis was performed using Student's t test (*, p < .05; **, p < .01; ***, p < .001). (C): Dose-response curves of the percentage of CD14+ cells in the presence of BM-MSCs (■) or AT-MSCs (○). (D): IL-10 concentrations in culture supernatants from day 6 of the monocyte differentiation in the presence of BM-MSCs and AT-MSCs are increased compared with the differentiation without MSCs. Data are means from three different experiments with six different BM-MSCs and three different AT-MSCs (MSC:monocyte ratio of 1:10); statistical analysis was performed using Student's t test (* indicates compared with control: **, p < .01; ***, p < .001; # indicates BM-MSCs compared with AT-MSCs: ##, p < .01). Abbreviations: AT-MSC, adipose tissue-derived multipotent stromal cells; BM-MSC, bone marrow-derived multipotent stromal cells; IL, interleukin; mono, monocyte; MSC, multipotent stromal cells; pos, positive.
Figure 5.
Figure 5.
AT-MSCs secrete higher levels of cytokines compared with BM-MSCs. (A): Cytokine concentrations measured in culture supernatant were higher for AT-MSCs compared with BM-MSCs. A representative experiment is shown from three separate experiments (n = 4 for both groups; IL-6 values represent 1.0 × 10−1 of the measured concentrations; IL-12 values shown are 10× the measured concentrations). (B): IL-6 mRNA expression was also increased in AT-MSCs compared with BM-MSCs (n = 3 for both groups). (C): AT-MSCs showed a slightly enhanced MTT activity; MTT activity of AT-MSCs is shown relative to that of BM-MSCs (n = 3 for both groups). Data are means ± SEM from three different experiments; statistical analysis was performed using Student's t test (*, p < .05; **, p < .01). Abbreviations: AT-MSC, adipose tissue-derived multipotent stromal cells; BM-MSC, bone marrow-derived multipotent stromal cells; IL, interleukin; IP-10, interferon γ-induced protein 10; MCP-1, monocyte chemotactic protein-1; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; TGF-b1, transforming growth factor-β1; VEGF, vascular endothelial growth factor.
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