Ameliorating role of microRNA-378 carried by umbilical cord mesenchymal stem cells-released extracellular vesicles in mesangial proliferative glomerulonephritis

Chen et al. Cell Communication and Signaling https://doi.org/10.1186/s12964-022-00835-1 (2022) 20:28 Open Access RESEARCH Ameliorating role of microRNA‑378 carried by umbilical cord mesenchymal stem cells‑released extracellular vesicles in mesangial proliferative glomerulonephritis Wenbiao Chen1,2,3*† , Feng Zhang4†, Xianliang Hou3, Huixuan Xu3 and Donge Tang3* Abstract Background: Mesenchymal stem cells (MSCs) and their released extracellular vesicles (Evs) have shown protective effects against kidney diseases. This study aims to study the functions of umbilical cord MSCs-released Evs (ucMSCEvs) and their implicated molecules in mesangial proliferative glomerulonephritis (MsPGN). Methods: A rat model of MsPGN was induced by anti-Thy-1.1, and rat mesangial cells (rMCs) HBZY-1 were treated with PDGF-BB/DD to mimic MsPGN condition in vitro. Rats and cells were treated with different doses of ucMSC-Evs, and then the pathological changes in renal tissues and proliferation of rMCs were determined. Differentially expressed microRNAs (miRNAs) after Evs treatment were screened by microarray analysis. The interactions among miR-378, PSMD14, and TGFBR1 were analyzed. Gain- and loss-of function studies of miR-378 and PSMD14 were performed to explore their effects on tissue hyperplasia and rMC proliferation and their interactions with the TGF-β1/Smad2/3 signaling pathway. Results: The ucMSC-Evs treatment ameliorated mesangial hyperplasia and fibrosis in rat renal tissues and suppressed the aberrant proliferation of rMCs in a dose-dependent manner. miR-378 was the most upregulated miRNA in tissues and cells after ucMSC-Evs treatment. miR-378 directly targeted PSMD14, and PSMD14 maintained the stability of TGFBR1 through deubiquitination modification, which led to TGF-β1/Smad2/3 activation. Either miR-378 knockdown or PSMD14 overexpression diminished the protective functions of ucMSC-Evs by activating the TGF-β1/Smad2/3 signaling pathway. *Correspondence: ; † Wenbiao Chen and Feng Zhang have contributed equally to this work. 1 Central Laboratory, People’s Hospital of Longhua, The Affiliated Hospital of Southern Medical University, Jianshe East Road, Longhua District, Shenzhen 518109, Guangdong, People’s Republic of China 3 Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, No. 1017 Dongmen North Road, Shenzhen 518020, Guangdong, People’s Republic of China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chen et al. Cell Communication and Signaling (2022) 20:28 Page 2 of 17 Conclusion: UcMSC-Evs ameliorate pathological process in MsPGN through the delivery of miR-378, which suppresses PSMD14-mediated TGFBR1 stability and inactivates the TGF-β1/Smad2/3 signaling pathway to reduce tissue hyperplasia and rMC proliferation. Keywords: Umbilical cord mesenchymal stem cells, Extracellular vesicles, Mesangial proliferative glomerulonephritis, microRNA-378, PSMD14, TGF-β1/Smad2/3 signaling pathway Graphical Abstract Background Mesangial proliferative glomerulonephritis (MsPGN) is characterized by the diffuse proliferation of mesangial cells (MCs) and deposition of mesangial matrix, which contributes to renal interstitial fibrosis, irreversible progressive glomerulosclerosis, and end-stage renal disease (ESRD) [1, 2]. MsPGN, takes up approximately 60% of all primary GN cases in China, is a predominant cause of chronic kidney disease, chronic renal failure, and uremia [3]. However, there are limited therapeutic options available for MsPGN treatment, and pharmacological interventions inhibiting MC proliferation and matrix accumulation are primary options to retard the GN progression [4]. Mesenchymal stem cells (MSCs) are progenitor multipotent cells abundantly existed in umbilical cord (uc) blood, adipose tissue, and bone marrow many tissues, which serve as an ideal candidate with therapeutic potentials owing to their secretory capacity, mainly including extracellular vesicles (Evs) [5]. MSCs participate in the repair of tissues, especially kidney, primarily by the release of Evs and their cargoes including lipids, microRNAs (miRNAs), mRNAs, and proteins [6, 7]. The functions of ucMSCs-derived Evs (ucMSC-Evs) in MsPGN are not fully explained. miRNAs are a major class of cargoes of Evs that maintain the normal function of human body conditions through the multipotent regulation in cell migration, proliferation, differentiation, and apoptosis [8]. However, aberrant expression of miRNAs is frequently correlated with many diseases including chronic kidney diseases [8]. Studies have reported that miRNAs can influence proliferation of glomerular MCs and accumulation of extracellular matrix (ECM) [9, 10]. In this study, miR-378 was screened as the most upregulated miRNA after administration of ucMSCs and therefore selected as the study subject. The transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (Smad) signaling pathway plays a crucial role in the prolonged glomerulosclerosis and the progression of chronic kidney diseases [11]. After binding to the TGF-β receptors (TGFBRs), TGF-β1 activates two critical downstream mediators, Smad2 and Smad3, to fulfill its functions including ECM production [12]. Interestingly, miR-378 has been reported to suppress mesangial hypertrophy, expression of collagens and α-smooth muscle actin (α-SMA) (biomarkers of ECM) in mice increased by TGF-β1 and Smad3 [13]. miRNAs are well known to govern gene expression to exert their functions. In the study, we found an enrichment of ubiquitinated protein degradation-related pathways by the predicted target mRNAs of miR-378. Among the miR-378 targets, proteasome 26S su (...truncated)