The role of stem cell-derived exosomes in regulating pyroptosis for disease therapy

Abstract

Pyroptosis, a form of programmed cell death, is widely involved in the occurrence and development of various diseases. Its mechanism relies primarily on the activation of pyroptosis proteins, making their expression levels crucial biological markers for assessing the degree of pyroptosis. In the progression of diseases, regulating pyroptosis can alleviate tissue damage and promote repair; in cancer treatment, inducing pyroptosis in cancer cells is also considered a potential therapeutic strategy. In recent years, acellular therapies have garnered significant attention in clinical research, with extracellular vesicles (EVs) (such as exosomes) emerging as novel acellular therapeutic tools. Exosomes exhibit remarkable potential for the treatment of various diseases, particularly in regulating pyroptosis. Owing to their diverse biological functions, exosomes derived from different sources of mesenchymal stem cells (MSCs) play distinct roles in treating different diseases. This review systematically summarizes the role and application prospects of MSC-derived exosomes in regulating pyroptosis for disease treatment. Studies have indicated that MSC-derived exosomes not only precisely regulate the process of pyroptosis but also offer new insights and methods for future disease therapies, and therefore, MSC-derived exosomes possess significant clinical translational value.

1. Introduction

Programmed cell death (PCD) is a genetically regulated form of cell death that is activated in response to external stimuli and plays a profound role in maintaining organismal homeostasis [1]. Distinct PCD subtypes exhibit characteristic features (Fig. 1). Specifically, pyroptosis is characterized by plasma membrane pore formation, cellular swelling, membrane rupture, and the release of proinflammatory cytokines [2], which ultimately trigger inflammatory responses. Apoptosis manifests as cell shrinkage, nuclear condensation, and the formation of apoptotic bodies that are phagocytosed by neighbouring cells or macrophages without inducing inflammation [3]. Necroptosis involves cellular and organellar swelling followed by plasma membrane rupture, which releases damage-associated molecular patterns (DAMPs) to initiate inflammation [4]. Autophagy features autophagosome formation; this process not only lacks proinflammatory effects but also may exert anti-inflammatory effects [5]. Ferroptosis is characterized by a reduction in/disappearance of the inner mitochondrial membrane and outer mitochondrial membrane rupture [6]. Among these forms of PCD, pyroptosis is particularly associated with immune defences and plays a critical role in bacterial infections and inflammatory diseases.

Owing to shared features with apoptosis—such as the involvement of caspase family proteins and nuclear condensation—pyroptosis was initially misclassified as apoptosis. However, with the elucidation of its underlying mechanisms and defining characteristics, the concept of pyroptosis was formally established [7]. During pyroptosis, plasma membrane rupture leads to the release of DAMPs and inflammatory cytokines (such as IL-1β and IL-18) into the extracellular environment, thereby eliciting an inflammatory response [8]. Under physiological conditions, pyroptosis serves as a crucial defence mechanism against pathogen invasion. However, excessive pyroptosis can result in uncontrolled inflammatory responses due to the massive release of inflammatory mediators [9]. In such cases, modulating pyroptosis is pivotal for disease regulation. Numerous studies have demonstrated that pyroptosis is closely linked to the pathological progression of various diseases, including ischaemic heart disease (IHD) [10], cancer [11, 12], neurodegenerative disorders [13], and diabetic nephropathy [14]. In these diseases, aberrant pyroptosis activation not only exacerbates inflammation but also contributes to tissue damage and disease progression.