Apoptotic MSCs and MSC-Derived Apoptotic Bodies as New Therapeutic Tools

Abstract

Over the past two decades, mesenchymal stem cells (MSCs) have shown promising therapeutic effects both in preclinical studies (in animal models of a wide range of diseases) and in clinical trials. However, the efficacy of MSC-based therapy is not always predictable. Moreover, despite the large number of studies, the mechanisms underlying the regenerative potential of MSCs are not fully elucidated. Recently, it has been reliably established that transplanted MSCs can undergo rapid apoptosis and clearance from the recipient’s body, still exhibiting therapeutic effects, especially those associated with their immunosuppressive/immunomodulating properties. The mechanisms underlying these effects can be mediated by the efferocytosis of apoptotic MSCs by host phagocytic cells. In this concise review, we briefly describe three types of MSC-generated extracellular vesicles, through which their therapeutic functions can potentially be carried out; we focused on reviewing recent data on apoptotic MSCs and MSC-derived apoptotic bodies (MSC-ApoBDs), their functions, and the mechanisms of their therapeutic effects.

Nanoghosts: Harnessing Mesenchymal Stem Cell Membrane for Construction of Drug Delivery Platforms Via Optimized Biomimetics

“…The development of MSC‐derived membranes as ghost carriers for nanoparticles are gradually showing interesting clinical potentials. MSC‐based therapies are already effective and biocompatible, despite several demerits live cell therapies could hold, like immunoregulatory problems, [ 22 ] local homeostasis disturbance, [ 17 ] rapid clearance, [ 23 ] and drug load inefficiency. [ 16 ] Nanoghost emergence was viewed as a great optimization and simplification of MSCs as nanoparticle carriers.…”

“…This phenomenon could be observed in tissue reparation, [13,14] immunoregulation, [15][16][17] tumorigenesis, [18][19][20] and even metastasis. [21][22][23] This unique capacity allows MSC to be developed into efficient tools for targeted drug carriers. They can serve directly as drug carriers, or be genetically modified through virus as vectors of gene cargoes.…”

Extracellular Vesicle-Based SARS-CoV-2 Vaccine

“…Exosomes are not formed directly from the cell membrane but are formed intracellularly and then secreted out of the cell. In addition, exosomes are formed by budding inside early endosomes from the cytoplasm, and ESCRT (endosomal sorting complex required for transport) and tetraspanins are involved in their formation [ 124 ]. In addition, endosomes containing many exosomes are called multivesicular bodies (MVB) because of their shape.…”

“…In fact, overexpression of nSMAse2/Smpd3 (neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3), a ceramide synthase, increases exosome secretion. Apoptotic vesicles, the largest heterogeneous population, are between 50 and 5000 nm in diameter and are generated from cell fragments during programmed cell death; they are produced by direct budding (shedding) from the cell membrane [ 124 , 125 , 126 ]. In addition, the existence of nanoparticles, called exomeres, with sizes of approximately 50 nm and without a membrane structure has also been reported [ 121 , 127 ].…”

Synergistic Hypoxia and Apoptosis Conditioning Unleashes Superior Mesenchymal Stem Cells Efficacy in Acute Graft-versus-Host-Disease

“…Therefore, this mechanism has been explored in a few studies by either inducing or inhibiting the apoptosis in MSCs by silencing the apoptotic effector molecules (BAK and BAX) in the MSCs and validating their therapeutic potential (10) and demonstrating that there was a reduction in their immunomodulatory capabilities in a viable form when administered in an asthmatic mice model, thereby potentiating the need for MSCs for undergoing apoptosis to exert their functional effect (10–12). Moreover, these apoptotic MSCs have been found to possess the ability to induce immunosuppressive effects in animal models of GVHD and various organ injuries like lung, liver, and spleen (6,13,14), suggesting that phagocytes are mediators of MSC-induced adaptive responses (15).…”