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  • Title: Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Faslpr mice.
    Author: Lee HK, Kim HS, Pyo M, Park EJ, Jang S, Jun HW, Lee TY, Kim KS, Bae SC, Kim Y, Hong JT, Yun J, Han SB.
    Journal: Theranostics; 2020; 10(22):10186-10199. PubMed ID: 32929342.
    Abstract:
    Rationale: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by autoantibody production by hyper-activated B cells. Although mesenchymal stem cells (MSCs) ameliorate lupus symptoms by inhibiting T cells, whether they inhibit B cells has been controversial. Here we address this issue and reveal how to prime MSCs to inhibit B cells and improve the efficacy of MSCs in SLE. Methods: We examined the effect of MSCs on purified B cells in vitro and the therapeutic efficacy of MSCs in lupus-prone MRL.Faslpr mice. We screened chemicals for their ability to activate MSCs to inhibit B cells. Results: Mouse bone marrow-derived MSCs inhibited mouse B cells in a CXCL12-dependent manner, whereas human bone marrow-derived MSCs (hMSCs) did not inhibit human B (hB) cells. We used a chemical approach to overcome this hurdle and found that phorbol myristate acetate (PMA), phorbol 12,13-dibutyrate, and ingenol-3-angelate rendered hMSCs capable of inhibiting IgM production by hB cells. As to the mechanism, PMA-primed hMSCs attracted hB cells in a CXCL10-dependent manner and induced hB cell apoptosis in a PD-L1-dependent manner. Finally, we showed that PMA-primed hMSCs were better than naïve hMSCs at ameliorating SLE progression in MRL.Faslpr mice. Conclusion: Taken together, our data demonstrate that phorbol esters might be good tool compounds to activate MSCs to inhibit B cells and suggest that our chemical approach might allow for improvements in the therapeutic efficacy of hMSCs in SLE.
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