Research reportExosomal microRNA-23b-3p from bone marrow mesenchymal stem cells maintains T helper/Treg balance by downregulating the PI3k/Akt/NF-κB signaling pathway in intracranial aneurysm
Introduction
Intracranial aneurysm (IA), also known as a cerebral aneurysm, is a dilatation of an artery that supplies blood to the brain and is one of the leading causes of subarachnoid hemorrhage (Tromp et al., 2014). Statistics show that the incidence of IA is about 3.2% in the general population (Nakaoka et al., 2014). It is reported that hemodynamic, genes, infection, ageing and congenital factors may relate to the occurrence and development of IA (Jin et al., 2013). A life-long follow-up study indicates that women are more likely to suffer an aneurysm rupture, and tobacco smoking is reported to be an important factor that results in the risk of rupture in patients with an unruptured IA (UIA) compared to UIA size factor (Korja et al., 2014). IA forms a complex disease with a poorly-understood molecular pathology.
Mesenchymal stem cells (MSCs) have been widely used in cell therapy and tissue engineering because of their self-renewal, multipotency, and immunomodulatory properties, which make them attractive tools for regenerative medicine (Dostert et al., 2017). A recent study demonstrates that intravenous administration of MSCs after aneurysm formation prevents aneurysmal rupture in mice (Kuwabara et al., 2017). It is noted that stem cells can release exosomes, and stem cell-derived exosomes are regarded as potential therapeutic targets for the paracrine actions of MSCs (Zhu et al., 2012). The exact effects of exosomes on aneurysm have been investigated (Wang et al., 2019b). Exosomes carrying proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs) can be transferred between cells (Lasser, 2012). miRNAs could regulate gene expression at the posttranscriptional level via degradation or repression of target mRNAs (Kim and Kim, 2013). In addition, the effects of miRNAs on IA have been investigated (Wei et al., 2018). The role of exosomal miRNAs in IA remains poorly understood.
A small amount of miRNAs have been confirmed to be actively involved in the regulation of tumor development (Corsini et al., 2012; Iorio and Croce, 2012). Decreased miR-23b is found in many kinds of cancers, including prostate cancer and glioma (Geng et al., 2012; Majid et al., 2012). In the present study, the microarray-based analysis showed that kruppel-like factor 5 (KLF5) is one of the target genes of miR-23b-3p. KLF5 is a zinc finger-containing transcription factor and has crucial roles in cell proliferation, apoptosis, migration, differentiation, and stemness in a context-dependent manner (McConnell et al., 2011; Sun et al., 2012). According to the literature report, the expression of KLF5 in IA model is upregulated, and miR-448 could prevent the malignant development of IA by inhibiting the expression of KLF5 (J. Z. Zhang et al., 2018). However, the effects of BMSCs-derived exosomes on the occurrence and progression of IA and their mechanisms remain poorly understood. Therefore, we intend to explore the roles of BMSCs-derived exosomal hsa-miR-23b-3p in IA with the involvement of KLF5 and the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt)/nuclear factor-kappa B (NF-κB) signaling pathway.
Section snippets
Ethics statemen
This study was approved and supervised by the ethics committee of Guangdong Second Provincial General Hospital. All the subjects signed the informed consents. Significant efforts were devoted to minimize both animal death and suffering.
Clinical samples
From March 2017 to March 2018, 36 IA patients (19 males and 17 females, with a median age of 21–67 and an average age of 45) were recruited as the model group. All the IA patients were tested using digital subtraction angiography (DSA). Arterial aneurysm samples
Imbalance of Th17/Treg is found in patients with IA
In this research, control group (brain trauma patients without vascular diseases) and model group (IA patients) were set. HE staining performed to evaluate pathomorphism of the artery tissue specimans from each group revealed that the control group had normal structure, complete endothelial and elastic layers, ordered media smooth muscle cells and little inflammatory cell infiltration; while the model group showed abnormal tissues in arterial aneurysm walls, thinning endothelial and elastic
Discussion
The occurrence and development of aneurysm involved complex pathological mechanism, but its molecular mechanism is not clear. In our study, we established rabbit models of IA and found a decrease in hsa-miR-23b-3p expression and an increase in KLF5 expression in the IA rats. We revealed that BMSCs-derived exosomes inhibited the activation of the PI3k/Akt/NF-κB signaling pathway and maintained Th17/Treg balance, which in turn interfered with aneurysm formation. KLF5 was found to be a major
Ethics statement
This study was performed with the approval of the Second Provincial General Hospital of Guangdong Province. All patients agreed and signed the informed consent. All procedures were strictly conducted in line with the code of ethics. Great efforts were made to minimize the animals and their pains.
Ethics approval
The present study was approved by the Committee of The the Second Provincial General Hospital of Guangdong Province (GZR-2019-KT-64−01).
CRediT authorship contribution statement
Xiaohui Sun: Conceptualization, Methodology, Writing - original draft. Xiaoxia Zheng: Investigation, Data curation. Xu Zhang: Formal analysis, Validation. Yang Zhang: Formal analysis, Writing - review & editing. Guoxuan Luo: Writing - review & editing, Funding acquisition.
Declaration of Competing Interest
All authors declare that there is no conflict of interests in this study.
Acknowledgement
This study was supported by the Science and Technology Planning Project of Guangzhou (201804010394).
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