The Protective Role of Exosomal circRNA-0008302 from Adipose-Derived Stem Cells (ADSCs) Against Myocardial Injury

doi:10.21203/rs.3.rs-1447181/v1

Download PDF

Research Article

The Protective Role of Exosomal circRNA-0008302 from Adipose-Derived Stem Cells (ADSCs) Against Myocardial Injury

https://doi.org/10.21203/rs.3.rs-1447181/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

This study aims to explore the expression of circRNA-0008302 in adipose stem cells derived exosome (ADSCs-Exo), and to investigate the function as well as mechanism of circRNA-0008302 in H₂O₂-induced cardiomyocyte injury.

Methods

Differentially expressed circRNAs between ADSCs and ADSCs-Exo were identified by circRNA chip screening, and further validated by qRT-PCR. CircRNA-0008302 siRNA was used to silence circRNA-0008302 expression in M6200 mouse cardiac myocytes. M6200 cells were divided into four groups: M6200 group, M6200 + H₂O₂ group, M6200 + H₂O₂ + ADSCs-Exo group and M6200 + H₂O₂ + ADSCs-Exo^{circ−0008302 siRNA} group. Thereafter, cell viability was evaluated using CCK8 assay. Apoptosis and intracellular ROS levels were measured by flow cytometry. The expression level of miR-466i-5p was evaluated by qRT-PCR. Western blotting was performed to detect MsrA protein expression.

Results

The expression of circ-0008302 was significantly increased in ADSCs-Exo compared with that in ADSCs. Through the delivery of circ-0008302, ADSCs-Exo maintained the viability, inhibited the apoptosis and reduced ROS production in cardiomyocytes, thereby protecting cardiomyocytes from H₂O₂-induced oxidative injury. Mechanistically, circ-0008302 downregulated the level of miR-466i-5p, and thus promoted the expression of a miR-466i-5p target gene-MsrA in cardiomyocytes.

Conclusion

ADSC-secreted exosomes have a protective role in myocardial injury by delivering circ-0008302, which increased MsrA expression via targeting miR-466i-5p in cardiomyocytes.

ADSC

adipose derived mesenchymal stem cell

exosome

circ-0008302

Apoptosis

Cardiovascular disease is one of the leading causes of death and disability worldwide. For the patients with myocardial infarction (MI), although myocardial reperfusion treatments like thrombolysis or percutaneous coronary intervention (PCI) are commonly adopted(1), in many cases these treatments are inefficient for preventing the occurrence of myocardial injury(2).

Stem cells play important roles in the repair and regeneration of damaged tissue, mainly achieved by paracrine secretion of tissue-regenerative factors(3). Recent reports suggested that stem cell-derived exosomes, which are membrane lipid nanovesicles with a diameter of 30–100 nm and serve as important mediators of intercellular signal transduction, contribute to tissue regeneration by delivering protective microRNAs (miRNAs) and proteins(4, 5).

Adipose-derived stem cells (ADSCs) are a type of stem cells which play pivotal functions in mediating tissue repair(6). ADSCs can secrete subcellular granules with a diameter of 20–100 nm, namely adipose stem cell-derived exosome (ADSCs-Exo). Compared with ADSCs, ADSCs-Exo has many advantages such as high stability as well as low antigenicity, and thus can provide a long-time protection. Therefore, ADSCs-Exo is comprehensively used in tissue damage-related disorders. Our previous studies have found that ADSCs-Exo can protect cardiomyocyte injury(7), but the mechanism of ADSCs-Exo's protection has not been clarified yet.

There are a wide variety of RNAs and proteins in ADSCs-Exo. Among them, circular RNAs (circRNAs) are endogenous non-coding RNA molecules, which have important regulatory roles in gene expression. CircRNAs are produced by back-splicing in which the 5’ end of a pre-mRNA upstream exon is non-colinearly spliced with the 3’ end of a downstream exon. Compared to miRNAs and mRNAs which have linear structure, circRNAs are resistant to exonuclease-mediated degradation since there is no 5’ cap and 3’ tail in their structure(8, 9). Hence, circRNAs are usually more stable than linear RNAs and thus can exert long-time biological effects. Mechanistically, circRNAs can act as ceRNAs to competitively influence the functions of miRNAs and their target genes in various pathological processes(10), including cardiovascular diseases. For example, circRNA_MFACR exacerbated myocardial infarction by upregulating MTP18 expression(11). CircRNA_NCX1 mediated myocardial injury by suppressing the function of miR-133a-3p and thus increasing the expression of CDIP1(12). CircRNA_000203 promoted cardiac hypertrophy by inhibiting miR26b-5p and miR-140-3p binding to Gata4(13). However, to date, the expression profile and therapeutic potential of ADSCs-Exo-derived circRNAs in cardiomyocyte injury are still elusive. In our present study, we screened differentially expressed circRNAs in ADSCs-Exo in order to explore the effects and mechanisms of ADSCs-Exo in cardiomyocyte injury. Hopefully this work can provide experimental basis for the clinical treatment and drug development of cardiomyocyte injury.

Differential circRNA screening and expression verification

M6200 cells were divided into experimental group and control group, ADSCs group and ADSCs-Exo group, and the total RNA of the two groups were purified and labeled with fluorescence, and the labeled products were purified. after that, chip hybridization, washing and scanning to obtain the circRNA chip and then validate the circRNAs identified by Quantitative Reverse Transcription PCR (qRT-PCR).

Construction and validation of circRNA siRNA plasmid

The obtained ADSCs-Exosomes and the differentially expressed circRNA in the exosomes were divided into two groups: control plasmid; circ-0008302 siRNA1；circ-0008302 siRNA2 and circ-0008302 siRNA3，at the same time ,validated the circRNAs identified by Quantitative Reverse Transcription PCR (qRT-PCR)

Effect of ADSCs-Exosomes and differentially expressed circRNA on H₂O₂ -induced cardiomyocyte injury

1）Detection of cell viability by CCK8

M6200 cells in logarithmic growth phase were plated into the 96-well plate with 100 μL DMEM medium per well. After cell adherence, the original medium was removed. According to the instruction, we treated the cells with CCK8 solution 10 μL/ well. and placed in an incubator and incubated for 4 hours. To get the cell viability, we measured the absorbance at 450 nm with a microplate reader.

2）Apoptosis of cells was measured by flow cytometry

M6200 cells were plated into 6-well plates and placed in a 5% CO2 cell incubator at 37℃ for 24 h. After cell adherence, and then the cells were treated according to the grouping principle for 24h, followed by centrifugation, washing and precipitation, and detected by flow cytometry. Finally, we used the CELL Quest software to analyze CELL apoptosis.

3）Detected the intracellular ROS levels, miRNA levels and MsrA expression levels

M6200 cells were plated into 6-well plates and placed in a 5% CO2 cell incubator at 37℃ for 24 hours. After cell adherence, and then the cells were treated according to the grouping principle for 24h, then digested with 0.25% trypsin without EDTA, and collected after termination of digestion. After centrifugation and washing, the ROS levels in each group were detected by flow cytometer. At the same time, qRT-PCR was also used to detect miRNA levels and WB was used to detect MsrA expression levels in cells.

Statistics

Quantitative data were obtained from the indicated number of experiments. The statistical significance of differences between multiple experimental groups was determined by one-way analysis of variance (ANOVA). P<0.05 was considered statistically significant.

Profiling the differentially expressed circRNAs.

ADSCs-Exo were obtained by using previously published methods(7). Firstly, we compared the circRNA expression profile between ADSCs and ADSCs-Exo using circRNA chip. Seven circRNAs with the most dramatic upregulation in ADSCs-Exo were selected from the differentially expressed circRNAs(Table 1).

Table 1 Differentially expressed circRNAs between ADSCs and ADSCs-Exo

circRNA-ID	hostgene	up/down
circ-0008302	Ralgps2	up
circ-0002468	Mknk2	up
circ-0002157	Rnf217	up
circ-0008982	Serpine2	up
circ-0008455	Rgs7	up
circ-0010012	Cacnb4	up
circ-0009075	Hdac4	up
circ0007490	Dcc	up

Among those, circ-0008302（host gene-Ralgps2）was reported to be highly expressed in the heart and played critical functions in cell proliferation, differentiation, and survival(14, 15); circ-0002468（host gene-Mknk2）could not design specific primers to detect; circ-0002157（host gene-Rnf217）is associated with poor prognosis of myeloma(16); circ-0008982（host gene- Serpine2）was reported to promote myocardial fibrosis(17, 18); circ-0008455（host gene-Rgs7）was induced in the dentate gyrus after ischemia(19); circ-0010012（host gene-Cacnb4）encodes a calcium channel subunit expressed in the heart and is important for myocardial contraction(20); circ-0009075（host gene-Hdac4）is related to myocardial exercise intensity and exercise could enhance HDAC4-NT levels(21); circ0007490（host gene-Dcc）is related to central nervous system dysfunction. The mutation of Dcc gene was reported to cause abnormal axon signal conduction(22). Based on the above backgrounds, we selected circ-0008302, circ-0010012 and circ-0007490 for the further validation by qRT-PCR.

Compared with the control group, the expression of circ-0007490 and circ-0010012 in ADSCs-Exo group was significantly decreased. In contrast, the expression of circ-0008302 was increased. Therefore, circ-0008302 was selected for the subsequent experiments (Figure 1).

Silencing circ-0008302 expression by siRNA.

To investigate the role of circ-0008302, we transfected M6200 mouse cardiac myocytes with circ-0008302 siRNA. Compared with control group, the expression of circ-0008302 was not significantly changed in cells transfected with control siRNA (siRNA-NC), while the expression of circ-0008302 was significantly decreased in cells transfected with circ-0008302 siRNA1-3, with siRNA2 having the most obvious effect, so the circ-0008302 siRNA2 was used in the subsequent experiments (Figure 2).

The effects of ADSCs-Exo and circ-0008302 in H₂O₂-induced cardiomyocytes injury.

To study the role of ADSCs-Exo and circ-0008302 in H₂O₂-induced cardiomyocyte damage, we tested the cell proliferation and apoptosis after different treatments. Compared with the control group, H₂O₂ treatment resulted in a reduction of viability of M6200 cardiac myocytes, which could be rescued by ADSCs-Exo. However, the protective role of ADSCs-Exo was abrogated by circ-0008302 knockdown (Figure 3A). Compared with the control group, H₂O₂ treatment increased cardiomyocyte apoptosis, while ADSCs-Exo treatment significantly reduced cell apoptosis. However, the anti-apoptotic role of ADSCs-Exo was significantly abrogated by circ-0008302 knockdown (Figure 3B-C). These results suggested that ADSCs-Exo could protect myocardium from ischemic injury, and this function is largely dependent on the circ-0008302 contained in ADSCs-Exo.

ADSCs-Exo can reduce the oxidative damage of cardiomyocytes through circ-0008302.

Cardiomyocyte damage caused by H₂O₂ is mainly due to the production of a large amount of ROS. Therefore, we tested whether ADSCs-Exo can reduce ROS production through circ-0008302 after H₂O₂ treatment of cardiomyocytes. Compared with the control group, H₂O₂ treatment increased the generation of intracellular ROS, which was reversed by ADSCs-Exo treatment. However, the knockdown of circ-0008302 abrogated the role of ADSCs-Exo in reducing intracellular ROS production (Figure 4A-B). Therefore, ADSCs-Exo prevents cardiac myocytes from oxidative damage, and this function is largely dependent on circ-0008302.

The protective effect of ADSCs-Exo and circ-0008302 is mediated by inhibiting the expression of miR-466i-5p to increase the expression of MsrA.

CircRNAs in exosomes often exert their effects by adsorbing miRNAs in cells. Therefore, we tried to find the downstream molecules of circ-0008302. According to the sequencing results, the circ-0008302 was predicted to bind to miR-466d-5p、miR-669f-3p、miR-466i-5p、miR-466b-3p and miR-466c-3p. Among those, miR-466d-5p and miR-466i-5p have more than one binding site. Through previous research results, we found that miR-466i-5p play crucial roles in various kinds of pathological processes including fibrosis(23), inflammation(24, 25), cancer(26) and metabolic disorders(27), while its function in cardiovascular diseases has never been investigated. Therefore, we selected miR-466i-5p for the following experiments.

Compared with the control group, the level of miR-466i-5p in cardiomyocytes treated with H₂O₂ was increased. ADSCs-Exo treatment significantly decreased the level of miR-466i-5p. However, the level of miR-466i-5p in ADSCs-Exo-treated cardiomyocytes was significantly increased by the knockdown of circ-0008302 (Figure 5A). The above results indicate that the efflux ADSCs-Exo of circ-0008302 can work by reducing the expression of miR-466i-5p induced by H₂O₂ challenge in cardiomyocytes. Finally, we explored the target gene of miR-466i-5p. It was predicted by Targets can database that the 3'-UTR of MsrA had the potential binding site of miR-466i-5p (Figure 5B). MsrA is an antioxidant factor that can negatively regulate NF-κB pathway and inhibit inflammatory response(28, 29). We then further validated the effect of miR-466i-5p on MsrA expression.

It can be seen from the results that compared with the control group, the level of MsrA in cardiomyocytes treated with H₂O₂ was decreased, ADSCs-Exo significantly reversed the effect of H₂O₂. Importantly, circ-0008302 knockdown significantly decreased MsrA expression in ADSCs-Exo-treated cardiomyocytes (Figure 5C-D). In summary, ADSCs-Exo serves as a positive regulator of MsrA expression in cardiomyocytes, this effect might be dependent on circ-0008302-mediated suppression of miR-466i-5p.

Cardiovascular disease is the main cause of death worldwide(1), and myocardial infarction is the most serious type of CVD with poor prognosis. Even after percutaneous coronary intervention and surgical treatment, myocardial ischemia- reperfusion can still cause myocardial cell apoptosis, hypertrophy, or other kinds of tissue injuries. Previous studies have found that adipose-derived stem cells (ADSCs) have biological functions to promote the repair and regeneration of damage tissues(6).The purpose of our research is to investigate the effect of ADSC-Exo on myocardial injury and explore the potential mechanisms from circRNA perspective. The results showed that through the delivery of circ-0008302, ADSCs-Exo can maintain the viability, inhibit the apoptosis and reduce ROS production of cardiomyocytes, thus protecting cardiomyocytes from H₂O₂-induced oxidative injury.

Studies have previously reported the potential efficacy of human umbilical cord mesenchymal stem cells (HUCMSCs) in repairing vascular injury(30, 31). Compare to HUCMSCs, ADSCs have some advantages because they are easier to obtain from large amounts of adipose tissue, and can rapidly expand in vitro. Exosomes, as a major paracrine component, are important mediators of intercellular signal transduction and play an important role in tissue repair by packaging and delivering RNA and protein. Compared to cells, cell-derived exosomes are safer and more convenient to deliver or storage. Due to these superiorities, ADSC-Exo has been widely used in the treatment of various diseases(32, 33).

In recent years, RNA therapy has emerged as a promising therapeutic option for cardiac regeneration and protection. As endogenous non-coding RNA molecules, circRNAs have been gaining increasing attention because they are resistant to exonuclease-mediated degradation and thus can provide a stable, long-time protection. In this work, we profiled the differentially expressed circRNAs between ADSCs and ADSCs-Exo, and identified circ-0008302 as a key mediator responsible for the protective role of ADSCs-Exo. In addition, the expression of circ-0007490 and circ-0010012 were also found to be significantly changed in ADSCs-Exo group. In contrast to circ-0008302, circ-0007490 and circ-0010012 was downregulated in ADSCs-Exo. Circ0007490 was reported to be involved in central nervous system dysfunction(22), while circ-0010012 was identified as a regulatory factor in Idiopathic Dilated Cardiomyopathy (IDC)(20). To date, their roles in the pathogenesis of myocardial injury remain known and deserve further investigation.

Mechanistically, circ-0008302 was found to target and inhibit miR-466i-5p expression. MiRNAs were found to be small (~ 22 nt) non-coding RNAs that negatively regulate the expression of protein-coding genes by inhibiting mRNA translation(34). MiRNA expression is associated with cardiac events, such as electrical signals, muscle contraction, heart growth and morphogenesis(35). Increasing evidence has shown that changes in miRNA expression profiles are commonly associated with heart disease such as myocardial infarction and heart failure(36). Thus, manipulating miRNA might achieve therapeutic effects in these diseases(37). In this study, it was confirmed that ADSCS-Exo inhibited the expression of miR-466i-5p by delivering circ-0008302, and thus maintaining the expression of a miR-466i-5p target gene-MsrA in H₂O₂-challenged cardiomyocytes. It is noteworthy that although miR-466i-5p has the highest binding score, it is not the only predicted miRNA with circ-0008302-binding capacity. The functions of other candidates such as miR-466d-5p, miR-669f-3p, miR-466i-5p, miR-466b-3p or miR-466c-3p still need careful examination in the future.

As a target gene of miR-466i-5p, MsrA was reported to participate in antioxidant defense, thereby protecting the host from tissue damage caused by inflammation or chemicals(28, 29). Since the excessive inflammatory response is the common driven factor contributing to the pathogenesis of myocardial injury. We speculated that the circ-0008302-mediated upregulation of MsrA might mitigate myocardial injury by suppressing cardiac inflammation. Further investigation is required for validating the exact mechanisms of action of MsrA in the future.

ADSC-secreted exosomes have a protective role in myocardial injury by delivering circ-0008302, which increased MsrA expression via targeting miR-466i-5p in cardiomyocytes.

It is only an experiment in vitro. Future experiments will be in vivo.

Acknowledgements

Not applicable.

Authors’ contributions

Chengyan Hu involved in data analysis, figures, and manuscript writing; Xipeng Sun involved in manuscript writing; Yanyan Chu and Yanling Wang carried out experiments; Zhi Liu involved in conception and design, edits and final approval. All authors read and approved the final manuscript. The authors read and approved the final manuscript.

Funding

This work was supported by grant no. 6217072649 from the Natural Science Foundation of China.

Availability of data and materials

Data available with Zhi Liu and Chengyan Hu.

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors and Institute given consent to publish the research data.

Conflict of interest

The authors declare that they have no conflict of interest.

Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Murray CJL, et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the Global Burden of Disease 2010 study. Circulation. 2014;129(14):1483–92.
Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Investig. 2013;123(1):92–100.
Jing H, He X, Zheng J. Exosomes and regenerative medicine: state of the art and perspectives. Translational research: the journal of laboratory and clinical medicine. 2018;196:1–16.
Eguchi S, Takefuji M, Sakaguchi T, Ishihama S, Mori Y, Tsuda T, et al. Cardiomyocytes capture stem cell-derived, anti-apoptotic microRNA-214 via clathrin-mediated endocytosis in acute myocardial infarction. J Biol Chem. 2019;294(31):11665–74.
Waldenström A, Ronquist G. Role of exosomes in myocardial remodeling. Circ Res. 2014;114(2):315–24.
Baer PC. Adipose-derived mesenchymal stromal/stem cells: An update on their phenotype in vivo and in vitro. World J Stem Cells. 2014;6(3):256–65.
Liu Z, Xu Y, Wan Y, Gao J, Chu Y, Li J. Exosomes from adipose-derived mesenchymal stem cells prevent cardiomyocyte apoptosis induced by oxidative stress. Cell Death Discov. 2019;5:79-.
Zhang Y, Xue W, Li X, Zhang J, Chen S, Zhang JL, et al. The Biogenesis of Nascent Circular RNAs. Cell Rep. 2016;15(3):611–24.
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495(7441):333–8.
Wang PL, Bao Y, Yee MC, Barrett SP, Hogan GJ, Olsen MN, et al. Circular RNA is expressed across the eukaryotic tree of life. PLoS ONE. 2014;9(6):e90859.
Wang K, Gan TY, Li N, Liu CY, Zhou LY, Gao JN, et al. Circular RNA mediates cardiomyocyte death via miRNA-dependent upregulation of MTP18 expression. Cell Death Differ. 2017;24(6):1111–20.
Li M, Ding W, Tariq MA, Chang W, Zhang X, Xu W, et al. A circular transcript of ncx1 gene mediates ischemic myocardial injury by targeting miR-133a-3p. Theranostics. 2018;8(21):5855–69.
Li H, Xu JD, Fang XH, Zhu JN, Yang J, Pan R, et al. Circular RNA circRNA_000203 aggravates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p binding to Gata4. Cardiovascular Res. 2020;116(7):1323–34.
Parrini AOS, Camonis MC. J. RalGPS2 Is Essential for Survival and Cell Cycle Progression of Lung Cancer Cells Independently of Its Established Substrates Ral GTPases. PLoS ONE. 2016;11(5):e0154840.
Ceriani M, Amigoni L, Scandiuzzi C, Berruti G, Martegani E. The PH-PxxP domain of RalGPS2 promotes PC12 cells differentiation acting as a dominant negative for RalA GTPase activation. Neurosci Res. 2010;66(3):290–8.
Zhou F, Wang D, Wei W, Chen H, Shi H, Zhou N, et al. Comprehensive profiling of circular RNA expressions reveals potential diagnostic and prognostic biomarkers in multiple myeloma. BMC Cancer. 2020;20(1):40.
Li X, Wang G, QiLi M, Liang H, Li T, E X, et al. Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology. 2018;45(5):1955–65.
Li X, Zhao D, Guo Z, Li T, Qili M, Xu B, et al. Overexpression of SerpinE2/protease nexin-1 Contribute to Pathological Cardiac Fibrosis via increasing Collagen Deposition. Sci Rep. 2016;6:37635.
Shelat PB, Coulibaly AP, Wang Q, Sun AY, Sun GY, Simonyi A. Ischemia-induced increase in RGS7 mRNA expression in gerbil hippocampus. Neurosci Lett. 2006;403(1–2):157–61.
Xu H, Dorn GW 2nd, Shetty A, Parihar A, Dave T, Robinson SW, et al. A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans. J Pers Med. 2018;8(1).
Lehmann LH, Jebessa ZH, Kreusser MM, Horsch A, He T, Kronlage M, et al. A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat Med. 2018;24(1):62–72.
Marsh APL, Edwards TJ, Galea C, Cooper HM, Engle EC, Jamuar SS, et al. DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome. Hum Mutat. 2018;39(1):23–39.
Hyun J, Park J, Wang S, Kim J, Lee HH, Seo YS, et al. MicroRNA Expression Profiling in CCl₄-Induced Liver Fibrosis of Mus musculus. International journal of molecular sciences. 2016;17(6).
Bao Y, Guo Y, Li Z, Fang W, Yang Y, Li X, et al. MicroRNA profiling in Muc2 knockout mice of colitis-associated cancer model reveals epigenetic alterations during chronic colitis malignant transformation. PLoS ONE. 2014;9(6):e99132.
Liu C, Zhang C, Yang J, Geng X, Du H, Ji X, et al. Screening circular RNA expression patterns following focal cerebral ischemia in mice. Oncotarget. 2017;8(49):86535–47.
Wang S, Xu Z, Wang L. Shuanghuang Shengbai granule cures myelosuppression and suppresses lung cancer progression: mechanism and therapeutic targets from the aspect of microRNAs. Oncotarget. 2017;8(37):62154–66.
Zhang Y, Fu Y, Zheng Y, Wen Z, Wang C. Identification of differentially expressed mRNA and the Hub mRNAs modulated by lncRNA Meg3 as a competing endogenous RNA in brown adipose tissue of mice on a high-fat diet. Adipocyte. 2020;9(1):346–58.
Singh MP, Kim KY, Kim HY. Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen. Biochem Biophys Res Commun. 2017;484(1):189–94.
Fan H, Li D, Guan X, Yang Y, Yan J, Shi J, et al. MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway. Drug design, development and therapy. 2020;14:1377-89.
Wang SH, Lin SJ, Chen YH, Lin FY, Shih JC, Wu CC, et al. Late outgrowth endothelial cells derived from Wharton jelly in human umbilical cord reduce neointimal formation after vascular injury: involvement of pigment epithelium-derived factor. Arterioscler Thromb Vasc Biol. 2009;29(6):816–22.
Liang CJ, Shen WC, Chang FB, Wu VC, Wang SH, Young GH, et al. Endothelial Progenitor Cells Derived From Wharton's Jelly of Human Umbilical Cord Attenuate Ischemic Acute Kidney Injury by Increasing Vascularization and Decreasing Apoptosis, Inflammation, and Fibrosis. Cell Transplant. 2015;24(7):1363–77.
Pu CM, Liu CW, Liang CJ, Yen YH, Chen SH, Jiang-Shieh YF, et al. Adipose-Derived Stem Cells Protect Skin Flaps against Ischemia/Reperfusion Injury via IL-6 Expression. J Invest Dermatol. 2017;137(6):1353–62.
Cui X, He Z, Liang Z, Chen Z, Wang H, Zhang J. Exosomes From Adipose-derived Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Wnt/β-Catenin Signaling Pathway. J Cardiovasc Pharmacol. 2017;70(4):225–31.
Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20(5):515–24.
Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007;129(2):303–17.
Abdellatif M. Differential expression of microRNAs in different disease states. Circ Res. 2012;110(4):638–50.
Barraclough JY, Joan M, Joglekar MV, Hardikar AA, Patel S. MicroRNAs as Prognostic Markers in Acute Coronary Syndrome Patients-A Systematic Review. Cells. 2019;8(12).

Download PDF

Version 1

posted

You are reading this latest preprint version

The Protective Role of Exosomal circRNA-0008302 from Adipose-Derived Stem Cells (ADSCs) Against Myocardial Injury

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Materials And Methods

Results

Discussion

Conclusion

Study Limitations

Declarations

References

Status:

Version 1