Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells

Luther, Kristin; Haar, Lauren; McGuinness, Myc; Wang, Yang; Lynch, Thomas; Phan, Anh Tuân; Song, Yang; Shen, Zhen; Gardner, George; Kuffel, Gina; Ren, Xiaoping; Zilliox, Michael J.; Jones, W. Keith

doi:10.1016/j.yjmcc.2018.04.012

Cited by 147 publications

(94 citation statements)

References 82 publications

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“…Conversely, Marquez et al [16] observed an inverse correlation between miR-21 and Peli1 mRNA levels during liver regeneration. In the myocardium, Luther et al [18] found that miR-21a-5p downregulated the expression of proapoptotic gene Peli1. At present, few researches focus on the association between miR-21 and Peli1, especially in autoimmune POI.…”

Section: Discussionmentioning

confidence: 99%

“…Yuan et al [17] demonstrated that low Peli1 and high miR-21-5p levels were observed in classical Hodgkin lymphoma (cHL) cell lines. In addition, Luther et al [18] showed that mesenchymal stem cell exosomes upregulated miR-21a-5p levels, thereby downregulating the expression of the proapoptotic genes Peli1, PDCD4, and PTEN in the myocardium. Peli1 has been reported to be abundantly expressed in T lymphocytes and functions as a negative regulator in T cell activation.…”

Section: Introductionmentioning

confidence: 99%

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miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

Xie

Wang

et al. 2020

Journal of Immunology Research

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Background. Premature ovarian insufficiency (POI) represents the hypergonadotropic hypoestrogenic symptoms that result in the loss of ovarian follicles. 5-30% POI cases are suggested to be involved in autoimmune etiology. MicroRNA-21 (miR-21) plays a vital role in ovarian folliculogenesis via regulating and interacting with multiple target genes. Here, we conduct the target prediction of miR-21, identify the expression and correlation of miR-21 and its putative target Pellino-1 (Peli1), and confirm their relationship with clinical characteristics in autoimmune POI. Methods. Bioinformatic analysis was conducted to screen the miR-21 putative target gene. Autoimmune POI mouse models were established by ZP3 immunization. Serum miR-21, Peli1 mRNA of peripheral blood mononuclear cells (PBMCs) and regulatory T cells (Tregs), general status, spleen Tregs ratio, inflammatory factors, ovarian endocrine function, and ovarian structure were evaluated. For autoimmune POI patients, serum miR-21, PBMCs Peli1 mRNA levels, general data, immune parameters, hormone levels, and ultrasound examinations were obtained. The correlations of miR-21 with Peli1 and clinical characteristics in patients were analyzed. Results. Peli1 was selected based on four microRNA prediction databases and literature retrieval. In mouse models, serum miR-21 level, PBMCs and Tregs Peli1 mRNA, and spleen Tregs ratio were 0.61±0.09, 0.12±0.12, 0.27±0.23 and 4.82±0.58, respectively, lower than those in the control group. In patients, miR-21 level (0.60±0.14) and Peli1 mRNA (0.30±0.14) were lower than those in the control group (1.01±0.07 and 1.63±0.54); miR-21 was positively related with Peli1, AMH, E2, the size of the uterus, and ovarian volume and negatively related with FSH, LH, and the number of positive immune parameters (AOAb, EMAb, ACL, ANA, ds-DNA, ACA, IgG, IgA, IgM, IgE, C3, and C4). Conclusions. Low expressions of miR-21 and Peli1 were detected in autoimmune POI mice and patients. Positive correlation between miR-21 and Peli1 was observed in autoimmune POI patients, suggesting that miR-21 and Peli1 might be associated with the pathogenesis of autoimmune POI.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

Xie

Wang

et al. 2020

Journal of Immunology Research

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“…In addition to promoting angiogenesis, EVs can also inhibit apoptosis, autophagy, and inflammatory regulation during cardioprotection. Luther et al 109 found that miRNA-21a-5p is the most abundant among several cardioprotective miRNAs through deep miRNA sequencing of MSC-EV cargo. Subsequent mechanistic studies found that miRNA-21 targeted the proapoptotic gene products PDCD4, PTEN, Peli1, and FasL in the myocardium, which in turn protected the myocardium by inhibiting ischemia-induced apoptosis.…”

Section: Msc-evs In Cardiovascular Disordersmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tissue Regeneration

et al. 2020

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Mesenchymal stem cells (MSCs) are multipotent stem cells that have attracted increasing interest in the field of regenerative medicine. Previously, the differentiation ability of MSCs was believed to be primarily responsible for tissue repair. Recent studies have shown that paracrine mechanisms play an important role in this process. MSCs can secrete soluble molecules and extracellular vesicles (EVs), which mediate paracrine communication. EVs contain large amounts of proteins and nucleic acids, such as mRNAs and microRNAs (miRNAs), and can transfer the cargo between cells. The cargoes are similar to those in MSCs and are not susceptible to degradation due to the protection of the EV bimolecular membrane structure. MSC-EVs can mimic the biological characteristics of MSCs, such as differentiation, maturation, and self-renewal. Due to their broad biological functions and their ability to transfer molecules between cells, EVs have been intensively studied by an increasing number of researchers with a focus on therapeutic applications, especially those of EVs secreted by MSCs. In this review, we discuss MSC-derived EVs and their therapeutic potential in tissue regeneration.

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“…We also found that miR-21 contributed to the improvement of cardiac function after DSAP-MSC-Exo injection in rat model of MI. miR-21 is a well-known cardioprotective microRNA, and it has been confirmed that exosomal miR-21 was a major cardioprotective paracrine factor produced by MSCs through the phosphatase and tensin homolog deleted on chromosome 10/Akt pathway (36,37). The latest data showed that miR-21 played a vital role in MSC-Exo-mediated effects on cardiac contractility and calcium handling, probably via PI3K signaling (38).…”

Section: Discussionmentioning

confidence: 91%

Self‐assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction

Cai

Wang

et al. 2019

FASEB j.

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The lower cell survival and retention in the hostile microenvironment after transplantation has been implicated as a major bottleneck in the advancement of stem cell therapy for myocardial infarction (MI). In this study, we designed a novel self‐assembling peptide (SAP) by attaching prosurvival peptide QHREDGS derived from angiopoeitin‐1 to the known SAP, RADA16‐I. The mesenchymal stem cells (MSCs) were harvested from male rats and cytoprotective effect of this designer SAP (DSAP) on cultured MSCs was detected by Hoechst 33342 staining after being exposed to oxygen and glucose deprivation (OGD). The cytoprotective effect of MSCs seeded in DSAP (DSAP‐MSCs) on OGD treated cardiomyocytes was examined by TUNEL staining, phosphorylated (p‐) protein kinase B (Akt) level, and ELISA. The therapeutic potential of MSC transplantation carried in DSAP was evaluated in a female rat MI model. PBS, MSCs alone, MSCs seeded in SAP (SAP‐MSCs), or DSAP‐MSCs were transplanted into the border of the infarcted area, respectively. DSAP not only increased the proliferation of MSCs and decreased apoptosis of MSCs after OGD treatment but also promoted the secretion of IGF‐1 and HGF in MSCs. Treatment with culture supernatant of DSAP‐MSCs markedly reduced the percentage of apoptotic cardiomyocytes and increased the level of p‐Akt. Compared with the MSC group and SAP‐MSC group, DSAP‐MSC injection improved cardiac function and reduced infarct size, collagen content, and cell apoptosis. The number of Y chromosome–positive cells and microvessels in the DSAP‐MSC group was higher than those in the MSC group and SAP‐MSC group. Moreover, DSAP‐MSC transplantation down‐regulated the expression of IL‐6 and IL‐1β and up‐regulated the level of VEGF and HGF. Interestingly, miR‐21 was enriched in DSAP‐MSC‐derived exosomes (DSAP‐MSC‐Exos) and the protection against cardiomyocyte apoptosis by DSAP‐MSC‐Exos was inhibited when miR‐21 was knocked down. Furthermore, miR‐21 contributed to the improvement of cardiac function after DSAP‐MSC‐Exo injection in a rat model of MI. Additionally, the combination of DSAP and cardiotrophin‐1 (Ctf1) pretreatment further improved the survival of MSCs and the efficiency of MSC transplantation. We proposed QHREDGS‐modified SAP as an effective cell delivery system and demonstrated that MSC transplantation in this DSAP promoted angiogenesis and paracrine, thereby reducing scar size and cell apoptosis as well as improving cardiac function probably via exosome‐mediated miR‐21 after MI. Furthermore, for the first time, we proposed that DSAP, especially working together with Ctf1 pretreatment, could be a valuable way to improve the survival of MSCs and the efficiency of MSC transplantation after MI.—Cai, H., Wu, F.‐Y., Wang, Q.‐L., Xu, P., Mou, F.‐F., Shao, S.‐J., Luo, Z.‐R., Zhu, J., Xuan, S.‐S., Lu, R., Guo, H.‐D. Self‐assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction. FASEB J. 33, 8306–8320 (2019). http://www.fasebj.org

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Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells

Cited by 147 publications

References 82 publications

miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tissue Regeneration

Self‐assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction

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