Synergistic potential of bone marrow mesenchymal stem cells and miR181-a combinational therapy against multiple sclerosis

Abstract

Background: Multiple sclerosis (MS) is a progressive autoimmune disease characterized by massive inflammatory infiltration, demyelination, and subsequent axonal injury and neuronal damage in the central nervous system (CNS). The etiology of MS remains unclear and there is not yet a definitive therapeutic schedule for the disease. Bone marrow mesenchymal stem cells (BMSCs), exhibiting neuroimmune-modulatory functions to alleviate various autoimmune diseases, show great potential in the treatment of MS. However, the instability of BMSCs-mediated immunosuppression in vivo has limited their application. MiR181-a, a positive regulator of immune balance, which has a preference for T cells and B cells differentiation, but degrade rapidly upon entering systemic circulation due to their unstable molecular structure. Methods: We propose a synergistic therapy approach that combines the penetrative targeting capability of BMSCs with the immuno-modulatory effects of miR181-a by overexpressing miR181-a to BMSCs through lentivirus packaging system. With this strategy, on the basis of the establishment of the experimental autoimmune encephalomyelitis (EAE) model, miR181-a overexpressing BMSCs (miR181a-BMSCs) would have a stronger immuno-modulatory treatment benefit, in terms of attenuating MS development. Results: Indicate that this method prolongs the modulatory effects of BMSCs and resulted in significantly enhancements of the proliferation of regulatory B cells (Bregs), regulatory T cells (Tregs) and the inhibition of Th17 cells compared to the traditional BMSCs group. Moreover, 10-fold miRNA’s concentration in the exosome of miR181a-BMSCs, leading to an increased duration of miRNAs to exert their biological effects. By immunotherapy and synergistic treatment, the effectiveness of the treatment is significantly enhanced, showing consistent results in different groups of the animal model.

1. Introduction

Multiple sclerosis (MS), a progressive autoimmune disease, is characterized by inflammation, demyelination, and neurodegeneration of the central nervous system (CNS) [1, 2]. Notably, the incidence and prevalence of MS are currently still on the rise, particularly among individuals aged 20 to 40 years [3]. At present, the treatment of MS is mainly symptomatic, which is often accompanied by a series of side effects, such as nausea, vomiting, and immune dysfunction [4, 5]. Therefore, new therapeutic methods are continually being explored to treat MS.

The experimental autoimmune encephalomyelitis (EAE) animal model is one of the most widely utilized animal models in MS research, as both the clinical and pathological characteristics were akin to those observed in MS [6]. B cells drive autoimmunity by serving as a source of pathogenic autoantibodies and cytokines [7]. Numerous studies have shown an inverse correlation between the quantity and functionality of the regulatory B cells (Bregs) and the severity of MS [8]. Currently, the specific role and mechanism of Bregs in MS remain inadequately understood. Bregs assist in activating of CD4+ T cells [7], directly inhibit the activity of pro-inflammatory T cells (Th1 and Th17 cells) through the secretion of the anti-inflammatory cytokine such as IL-10 [9], and facilitate the conversion of T cells into regulatory T cells (Tregs) [10]. In the investigation of MS treatment, growing evidence indicates that the dysregulation of B cells and T cells, particularly their regulatory roles in inflammation and immune response [11–13]. Consequently, current studies focus on exploring the induction, function, and regulation of B cells and T cells in MS [14], aiming to identify more effective therapeutic strategies that modulate their interaction and alleviate MS. Despite considerable efforts, current therapeutic strategies remain limited. Thus, modulating or restoring the immunomodulatory function of Bregs to influence the balance of inflammatory factors and the interaction between Th17 cells and Tregs may offer a promising therapeutic approach.