Abstract
Objective Lupus nephritis is the most common and severe complication of systemic lupus erythematosus. The aim of our study was to investigate the efficacy of miR-20a overexpressing adipose-derived stem cell (ADSC) transplantation in murine lupus nephritis (LN) and explore potential molecular mechanisms. Methods Mouse ADSCs were transfected with a miR-20a lentiviral vector to obtain miR-20a overexpression ADSCs (miR-20a-ADSCs). We first observed the influence of miR-20a on ADSC viability and apoptosis in vitro. B6.MRL/lpr mice were administered ADSC/miR-20a-ADSC intravenously every week from age 30 to 33 weeks, and the lupus and normal control groups received PBS on the same schedule. Results miR-20a expression increased in miR-20a-ADSC-derived exosomes, and miR-20a overexpression promoted ADSC proliferation and inhibited apoptosis. Compared with ADSCs, miR-20a-ADSC treatment significantly improved serologic and histologic abnormalities, as evidenced by reduced serum creatinine, anti-dsDNA antibody, 24 h urine protein levels, nephritis scores, and C3/IgG deposits. Furthermore, miR-20a-ADSC treatment resulted in downregulated Akt, mTOR, and p62 expression and upregulated miR-20a, Beclin 1, and LC3 II/I expression compared with ADSC treatment. After treatment with miR-20a-ADSC, a significant increase in the number of autophagosomes within podocytes was observed, along with upregulated expression of podocin and nephrin, compared with the ADSC group. Conclusions miR-20a-ADSC transplantation prevents the development of lupus nephritis and significantly ameliorates already-established disease, and its mechanism is related to autophagy by targeting the miR-20a-regulated mTOR pathway.
Highlights
Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease that affects multiple organs and systems, has limited treatment options, and has no cure
This study offers a novel therapeutic method to enhance the efficacy of adipose-derived stem cell (ADSC) in SLE
Results miR-20a overexpression increases ADSC proliferation and inhibits apoptosis in vitro; miR-20a expression levels increased in miR-20a-ADSC-derived exosomes
Summary
Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease that affects multiple organs and systems, has limited treatment options, and has no cure. The standard therapy for LN patients includes immunosuppressive regimens and corticosteroids. Within 10 years of an initial SLE diagnosis, 5%–20% of patients with LN develop end-stage kidney disease, and multiple comorbidities associated with immunosuppressive treatment, including infections, osteoporosis, and cardiovascular and reproductive effects, remain a concern [2]. Considering these factors, more effective therapies are needed. Current evidence demonstrates that MSCs release a type of specialized extracellular vesicle known as exosomes to provide therapeutic benefits. Exosomes are membranous nanosized vesicles secreted by a variety of cells, merging their membrane contents into the recipient cell membrane and transferring
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