Theranostics 2020; 10(22):10186-10199. doi:10.7150/thno.46835 This issue Cite

Research Paper

Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Faslpr mice

Hong Kyung Lee1*, Hyung Sook Kim1*, Minji Pyo1, Eun Jae Park1, Sundong Jang1, Hye Won Jun1, Tae Yong Lee1,2, Kyung Suk Kim2, Sang-Cheol Bae3, Youngsoo Kim1, Jin Tae Hong1, Jaesuk Yun1✉, Sang-Bae Han1✉

1. College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea.
2. Bioengineering Institute, Corestem Inc., Gyeonggi 13486, Republic of Korea.
3. Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Republic of Korea.
*These authors contributed equally to this study.

Citation:
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. Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Faslpr mice. Theranostics 2020; 10(22):10186-10199. doi:10.7150/thno.46835. https://www.thno.org/v10p10186.htm
Other styles

File import instruction

Abstract

Graphic 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.

Keywords: B cell, CXCL10, mesenchymal stem cell, PD-L1, phorbol ester, systemic lupus erythematosus


Citation styles

APA
Lee, H.K., Kim, H.S., Pyo, M., Park, E.J., Jang, S., Jun, H.W., Lee, T.Y., Kim, K.S., Bae, S.C., Kim, Y., Hong, J.T., Yun, J., Han, S.B. (2020). Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Faslpr mice. Theranostics, 10(22), 10186-10199. https://doi.org/10.7150/thno.46835.

ACS
Lee, H.K.; Kim, H.S.; Pyo, M.; Park, E.J.; Jang, S.; Jun, H.W.; Lee, T.Y.; Kim, K.S.; Bae, S.C.; Kim, Y.; Hong, J.T.; Yun, J.; Han, S.B. Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Faslpr mice. Theranostics 2020, 10 (22), 10186-10199. DOI: 10.7150/thno.46835.

NLM
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. Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Faslpr mice. Theranostics 2020; 10(22):10186-10199. doi:10.7150/thno.46835. https://www.thno.org/v10p10186.htm

CSE
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. 2020. Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Faslpr mice. Theranostics. 10(22):10186-10199.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image