New Approaches for Enhancement of the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cardiovascular Diseases

Abstract

Cardiovascular diseases (CVDs) remain a major health concern worldwide, where mesenchymal stem cells (MSCs) therapy gives great promise in their management through their regenerative and paracrine actions. In recent years, many studies have shifted from the use of transplanted stem cells to their secreted exosomes for the management of various CVDs and cardiovascular-related diseases including atherosclerosis, stroke, myocardial infarction, heart failure, peripheral arterial diseases, and pulmonary hypertension. In different models, MSC-derived exosomes have shown beneficial outcomes similar to cell therapy concerning regenerative and neovascular actions in addition to their anti-apoptotic, anti-remodeling, and anti-inflammatory actions. Compared with their parent cells, exosomes have also demonstrated several advantages, including lower immunogenicity and no risk of tumor formation. However, the maintenance of stability and efficacy of exosomes after in vivo transplantation is still a major concern in their clinical application. Recently, new approaches have been developed to enhance their efficacy and stability including their preconditioning before transplantation, use of genetically modified MSC-derived exosomes, or their utilization as a targeted drug delivery system. Herein, we summarized the use of MSC-derived exosomes as therapies in different CVDs in addition to recent advances for the enhancement of their efficacy in these conditions. Graphical abstract

Recent clinical trials with stem cells to slow or reverse normal aging processes

“…The Chinese clinical trial database ( chictr.org.cn/searchprojen.aspx ) included a clinical trial with MSC-derived exosomes for photoaging (ChiCTR2200061216; see Section 3.2.3.2; Table 2 ). Interestingly, the exosomes used were loaded with circular RNA, a genetic modification procedure that can improve therapeutic efficacy [for information on genetic modification, preconditioning and engineering of MSC-derived exosomes, see ( Ahmed and Al-Massri, 2022 ; Chen et al, 2022 )].…”

Mesenchymal Stem Cell-Derived Exosomes for Myocardial Infarction Treatment

“…Therefore, modifying and optimizing exosomal content in MSC-EXO in vitro prior to transplantation to enhance their therapeutic efficacy for MI is vital. Over the past decades, several novel strategies, including altering culture conditions and pretreatment with pharmacological compounds and molecules, have been explored to generate modified MSC-EXO with greater benefits for MI treatment [56,101]. More importantly, genetic modification of MSCs has had a great impact on the release of MSC-EXO, directly modulating their therapeutic efficacy.…”

“…Accumulating evidence shows that EXO from hypoxia-primed MSCs used to treat MI are superior to EXO from MSCs cultured under normoxic conditions [63,105,106]. Hypoxic preconditioning can enrich some specific miRNAs in the MSC-EXO that protect against MI by promoting angiogenic potential, attenuating inflammation and ameliorating apoptosis of cardiomyocytes [101]. It has been documented that hypoxic preconditioning of MSC-EXO elicits better therapeutic efficacy for MI by reducing the apoptosis of cardiomyocytes via upregulation of miR-210 that targets AIFM3 protein [75].…”

Regulation of Extracellular Vesicle-Mediated Immune Responses against Antigen-Specific Presentation

“…To date, clinical trials have been conducted using MSCs as novel therapeutic agents to treat various diseases, including acute diseases, such as ischaemic stroke and myocardial infarction. MSCs are also intended anti-inflammatory therapy for diseases caused by uncontrolled inflammatory reactions, such as acute graft-versus-host disease (GvHD) and Crohn’s disease [ 329 , 330 , 331 , 332 ].…”