Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Fas(lpr) miceopen access
- Authors
- Lee, Hong Kyung; Kim, Hyung Sook; Pyo, Minji; Park, Eun Jae; Jang, Sundong; Jun, Hye Won; Lee, Tae Yong; Kim, Kyung Suk; Bae, Sang-Cheol; Kim, Youngsoo; Hong, Jin Tae; Yun, Jaesuk; Han, Sang-Bae
- Issue Date
- 2020
- Publisher
- IVYSPRING INT PUBL
- Keywords
- B cell; CXCL10; mesenchymal stem cell; PD-L1; phorbol ester; systemic lupus erythematosus
- Citation
- THERANOSTICS, v.10, no.22, pp.10186 - 10199
- Indexed
- SCIE
SCOPUS
- Journal Title
- THERANOSTICS
- Volume
- 10
- Number
- 22
- Start Page
- 10186
- End Page
- 10199
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/11543
- DOI
- 10.7150/thno.46835
- ISSN
- 1838-7640
- 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.Fas(lpr) 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 naive hMSCs at ameliorating SLE progression in MRL.Fas(lpr) 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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