Unleashing the therapeutic potential of apoptotic bodies

Abstract

Extracellular vesicles (EVs), membrane-bound vesicles that are naturally released by cells, have emerged as new therapeutic opportunities. EVs, particularly exosomes and microvesicles, can transfer effector molecules and elicit potent responses in recipient cells, making them attractive therapeutic targets and drug delivery platforms. Furthermore, containing predictive biomarkers and often being dysregulated in various disease settings, these EVs are being exploited for diagnostic purposes. In contrast, the therapeutic application of apoptotic bodies (ApoBDs), a distinct type of EVs released by cells undergoing a form of programmed cell death called apoptosis, has been largely unexplored. Recent studies have shed light on ApoBD biogenesis and functions, promisingly implicating their therapeutic potential. In this review, we discuss many strategies to develop ApoBD-based therapies as well as highlight their advantages and challenges, thereby positioning ApoBD for potential EV-based therapy.

Keywords: apoptosis; apoptotic bodies; extracellular vesicles; therapeutics.

Figure 1.. Extracellular vesicle (EV) formation and cargo packaging.

Healthy cells release two major EV subtypes, namely exosomes through exocytosis of multivesicular bodies and microvesicles through plasma membrane shedding (upper panel). Apoptotic cells generate apoptotic bodies (ApoBDs) via apoptotic cell disassembly with three distinct morphological changes: (i) membrane blebbing, (ii) formation of thin membrane protrusion including apoptopodia and beaded-apoptopodia and (iii) fragmentation of membrane protrusion to form distinct ApoBDs. ApoBD biogenesis is regulated by caspase-cleaved substrates, including ROCK1, which phosphorylates and activates blebbing-regulating myosin light-chain (MLC), and PLXB2 (positive regulators) as well as ATP channel PANX1 (negative regulator). Various cellular biomolecules, including nucleic acids and proteins, can be packed into ApoBDs, exosomes and microvesicles, which aid intercellular communications. CASP-3/7, caspases 3 and 7; ROCK1, Rho-associated kinase 1; MLC, myosin light-chain; MLC-P, phosphorylated myosin light-chain; PANX1, pannexin 1; PLXB2, plexin B2.

Figure 2.. Strategies to leverage ApoBDs for therapeutic development.

ApoBDs are rapidly and efficiently engulfed by tissue-resident professional phagocytes (e.g. macrophages and immature dendritic cells) or by neighbouring non-professional phagocytes. (A) Defective ApoBD and apoptotic cell clearance have been linked to inflammation and autoimmunity due to subsequent secondary necrosis and ApoBD lysis, causing leakage of autoantigens. Pharmacological promotion of ApoBD formation, e.g. via PANX1 inhibition, to aid cell clearance may provide therapeutic relief for clearance-associated diseases. (B) ApoBDs derived from infected cells may contain infectious agents for infection propagation, which could be pharmacologically blocked through the inhibition of the positive regulator of ApoBD formation (e.g. ROCK1). (C) Depending on the cargo materials (e.g. pathogen-derived materials, oncogenes, autoantigens), ApoBDs may or may not induce maturation of engulfing dendritic cells (through the expression of maturation markers CD40, CD80, etc.), respective leading to (i) immunogenic response via antigen presentation-mediated T cell activation or (ii) immunotolerogenic response through the secretion of TGF-β and activation of regulatory T cells. Therefore, ApoBDs and cargo packaging can potentially be manipulated to deliver desired immunotherapeutic outcomes. (D) ApoBDs, such as those derived from stem cells, carry signalling effectors that can promote survival, proliferation and differentiation in engulfing non-professional phagocytes, paving ways to the promising exploitation of stem cell-derived ApoBDs for regenerative therapies. CD40, cluster of differentiation 40; CD80, cluster of differentiation 80; TGF-β, transforming growth factor β; MHCI, major histocompatibility complex I; APC, antigen-presenting cell; NPC, non-professional phagocyte.