Full Text | PDF

Theranostics 2021; 11(2):893-905. doi:10.7150/thno.48080 This issue Cite

Research Paper

Human umbilical cord-derived mesenchymal stem cell therapy ameliorates lupus through increasing CD4+ T cell senescence via MiR-199a-5p/Sirt1/p53 axis

Tao Cheng^1*, Shuai Ding^1*, Shanshan Liu¹, Yan Li^2✉, Lingyun Sun^1✉

1. Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008 China
2. The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center, Model Animal Research Center of Nanjing University, Nanjing, 210061 China
*Contributed equally to this work.

✉ Corresponding authors: Lingyun Sun, MD, PhD, Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008 China. Email: lingyunsunedu.cn; Yan Li, PhD, The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu 210061, China. Email: yanliedu.cn. More

Abstract

Rationale: Although human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation has been proved to be an effective therapeutic approach to treat systemic lupus erythematosus (SLE), the detailed underlying mechanisms are not fully understood. Transferring miRNAs is one mean by which MSCs communicate with surrounding cells. Sirt1 is a NAD-dependent deacetylase that protects against cell senescence by deacetylating p53. Here we aimed to explore whether hUC-MSCs affected senescence of splenic CD4+ T cells through regulating Sirt1/p53 via miRNA in the MRL/lpr lupus mouse model.

Methods: The effects of hUC-MSCs on lupus syndrome and senescence pathways in MRL/lpr mice in vivo and in vitro were determined. The functional roles of miR-199a-5p in splenic CD4+ T cell senescence were studied by miRNA mimic or inhibitor in vitro. MRL/lpr mice were injected with miR-199a-5p agomir to evaluate the effects of miR-199a-5p on splenic CD4+ T cell senescence and disease in vivo.

Results: We showed that hUC-MSCs transplantation ameliorated lupus symptoms and increased senescence of splenic CD4+ T cells through Sirt1/p53 signaling via miR-199a-5p in MRL/lpr mice. Moreover, systemic delivery of miR-199a-5p in MRL/lpr mice increased splenic CD4+ T-cell senescence, mimicking the therapeutic effects of transplanted hUC-MSCs.

Conclusions: We have identified miR-199a-5p as one of the mechanisms employed by hUC-MSCs to alleviate lupus disease associated pathologies in MRL/lpr mice, which is attributable for promoting splenic CD4+ T cell senescence through Sirt1/p53 pathway.

Keywords: Mesenchymal stem cells, Lupus, Senescence, Sirt1/p53, miR-199a-5p

Citation styles

©2024 Ivyspring International Publisher. Terms of use