Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles: A focus on inflammatory bowel disease

Abstract

Background: Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC-EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro-regenerative, anti-apoptotic, and antifibrotic properties. Consequently, MSC-EVs represent a cell-free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non-immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage.

Main topics covered: This review aims to provide a comprehensive examination of the therapeutic efficacy of MSC-EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC-EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC-EV cargoes. We also discuss available preclinical studies demonstrating that MSC-EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials.

Conclusions: Finally, we highlight the potential of MSC-EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice.

Highlights: The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC-derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose-derived MSC-EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD). MicroRNAs are consistently present in MSC-EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR-let-7a is associated with inhibition of apoptosis, miR-100 supports cell survival, miR-125b helps suppress pro-inflammatory cytokines and miR-20 promotes anti-inflammatory M2 macrophage polarisation. Preclinical studies in IBD models have shown that MSC-EVs reduce intestinal inflammation by suppressing pro-inflammatory mediators (e.g., TNF-α, IL-1β, IL-6) and increasing anti-inflammatory factors (e.g., IL-4, IL-10). They also promote mucosal healing and strengthen the integrity of the gut barrier, suggesting their potential to address IBD pathology.

Keywords: Crohn's disease; exosomes; nanomedicine; ulcerative colitis.

FIGURE 1

Immune dysregulation and barrier dysfunction in the pathogenesis of inflammatory bowel disease (IBD). The disruption of intestinal homeostasis in IBD is driven by dysbiosis in the gut lumen, loss of the mucus layer, and increased epithelial permeability, allowing bacterial translocation into the lamina propria. Breaches in the epithelial barrier activate dendritic cells, which migrate to mesenteric lymph nodes and promote the differentiation of naïve T cells into pro‐inflammatory T helper (Th) cell subsets. Under healthy conditions, regulatory T cells (Tregs) maintain immune homeostasis by secreting anti‐inflammatory cytokines such as IL‐10 and TGF‐β. In IBD, this balance shifts toward pro‐inflammatory Th cells, resulting in elevated levels of cytokines including TNF‐α, IL‐1β, IL‐6, IL‐17 and IL‐23. Additionally, dysregulated innate lymphoid cells (ILCs) exacerbate IBD by producing IL‐23, which stimulates IL‐17 secretion, further driving inflammation.

FIGURE 2

Mesenchymal stem cell (MSC) secretome. This figure depicts the diverse bioactive components secreted by MSCs, collectively referred to as the MSC‐secretome. The secretome is divided into two primary fractions: the soluble fraction, which includes proteins and soluble factors such as cytokines, growth factors and chemokines; and the vesicular fraction, which encompasses exosomes, microvesicles and apoptotic bodies. Exosomes (30‒200 nm) are generated through endocytosis, microvesicles (200‒1000 nm) are released directly from the plasma membrane via budding, and apoptotic bodies (1000‒5000 nm) are large vesicles formed during apoptosis.

FIGURE 3

Mechanisms of mesenchymal stem cell‐derived extracellular vesicles and their therapeutic effects in inflammatory bowel disease. This figure illustrates the mechanisms through which mesenchymal stem cell‐derived extracellular vesicles exert therapeutic effects in inflammatory bowel disease. Key pathways include modulation of the immune response, reduction of inflammation, promotion of tissue repair and improvement of intestinal barrier function.

FIGURE 4

Therapeutic effects of mesenchymal stem cell‐derived extracellular vesicles in preclinical studies of inflammatory bowel disease. Illustration of the mechanisms of mesenchymal stem cell‐derived extracellular vesicles and their therapeutic effects on inflammatory bowel disease in preclinical studies, achieved by suppressing pro‐inflammatory cytokines and increasing the levels of anti‐inflammatory mediators.

FIGURE 5

Representative results of the analysis of Table 3, summarising a total of 19 ongoing and completed clinical trials using mesenchymal stem cell‐derived extracellular vesicles. The number of trials corresponding to each section is displayed inside the boxes. (A) Route of administration of mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs). (B) Trial status provided by clinicaltrials.gov. (C) Trial phase provided by clinicaltrials.gov. (D) Source of MSC‐EVs used in each trial. (E) Organs targeted for administration of MSC‐EVs. N.D., not determined; Recr., recruiting.