Int J Stem Cells.  2020 Jul;13(2):237-245. 10.15283/ijsc20001.

SOCS1 Regulates the Immunomodulatory Roles of MSCs on B Cells

• Zhang L
• Qu YN
• Zhang HY
• Wu ZY
• Li ZL
• Guo WB
• Wang QB
• Fang NZ
• Jiang XX

• KMID: 2504336
• DOI: http://doi.org/10.15283/ijsc20001

Abstract

Background and Objectives
The effective use of MSCs for the treatment of some B cell-mediated immune diseases is quite limited. The main reason is that the immunomodulatory effects of mesenchymal stem cells (MSCs) on B cells are unclear, and their underlying mechanisms have not been fully explored.
Methods and Results
By co-culturing B cells with MSCs without (MSC/CTLsh) or with suppressor of cytokine signaling 1 (SOCS1) knockdown (MSC/SOCS1sh), we found that MSCs inhibited B cell proliferation, activation and terminal differentiation. Remarkably, the highest inhibition of B cell proliferation was observed in MSC/SOCS1sh co-culture. Besides, MSC/SOCS1sh reversed the inhibitory effect of MSCs in the last stage of B cell differentiation. However, MSC/SOCS1sh had no effect on inhibiting B cell activation by MSCs. We also showed that IgA+ B cell production was significantly higher in MSC/SOCS1sh than in MSC/CTLsh, although no difference was observed when both MSCs co-cultures were compared to isolated B cells. In addition, MSCs increased PGE2 production after TNF-α/IFN-γ stimulation, with the highest increase observed in MSC/SOCS1sh co-culture.
Conclusions
Our results highlighted the role of SOCS1 as an important new mediator in the regulation of B cell function by MSCs. Therefore, these data may help to develop new treatments for B cell-mediated immune diseases.

Keyword

MSCs immunomodulation; SOCS1; B cell

Figure

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  Fig. 1 SOCS1 knockdown aggravates the inhibitory effect of MSCs on B cell proliferation. The B cells isolated from the mouse spleens were labeled with CFSE and stimulated with LPS (A), LPS+IL4 (B), LPS+TGFβ (C) for 22 hours and then cultured alone or co-cultured with different ratios of MSC/CTLsh or MSC/SOCS1sh under the stimulation of the above cytokines. After 36 hours of co-culture, the B cell proliferation was analyzed by flow cytometry. Data were representative of three independent experiments. *p<0.05, **p<0.01, ***p<0.001. Note: CTLsh, MSC/CTLsh; SOCS1sh, MSC/SOCS1sh.

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  Fig. 2 SOCS1sh has no effect on the inhibition of B cell activation by MSCs. B cells isolated from mouse spleens were stimulated with LPS (A), LPS/IL4 (B) and LPS/TGFβ (C) for 11 hours and then co-cultured by adding MSC/CTLsh or MSC/SOCS1sh at a ratio of 1：10. After 9 hours of co-culture, B cells were labeled with anti-CD40 and anti-CD86 antibodies. B cell activation was analyzed by flow cytometry. Note: CTLsh, MSC/CTLsh; SOCS1sh, MSC/SOCS1sh.

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  Fig. 3 Knockdown of SOCS1 reverses the inhibition of plasma cell formation by MSCs. B cells were stimulated with LPS (A), LPS/IL4 (B), LPS/TGFβ (C) for 23 hours and then co-cultured by adding MSC/CTLsh or MSC/SOCS1sh at a ratio of 1：10. After two days of co-cultivation, B cells were harvested, labeled with anti-B220 and anti-CD138 antibodies and analyzed for plasma cell formation by flow cytometry. Data were representative of three independent experiments. *p<0.05. Note: CTLsh, MSC/CTLsh; SOCS1sh, MSC/SOCS1sh.

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  Fig. 4 MSC/SOCS1sh promotes IgA+ B cell formation. Purified B cells were stimulated with LPS for 24 hours, then MSC/CTLsh or MSC/SOCS1sh was added at a ratio of 1：10 and co-cultured for 3 days. All cultures were stimulated with LPS. After co-cultivation for 3 days, the percentages of IgA+ B cells were determined by FACS, which are showed within the squares. Data were representative of three independent experiments. *p<0.05. Note: CTLsh, MSC/CTLsh; SOCS1sh, MSC/SOCS1sh.

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  Fig. 5 SOCS1 knockdown promotes PGE2 secretion by MSCs. MSC/CTLsh or MSC/SOCS1sh were stimulated with different doses (0, 0.5 and 5 ng/ml) of TNF-α/IFN-γ for 12 h and then the level of PGE2 in the culture medium was measured by ELISA. Data were representative of three independent experiments. **p<0.01. Note: CTLsh, MSC/CTLsh; SOCS1sh, MSC/SOCS1sh.

Reference

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