Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock

Abstract

Severe trauma is the principal cause of death among young people worldwide. Hemorrhagic shock is the leading cause of death after severe trauma. Traumatic hemorrhagic shock (THS) is a complex phenomenon associating an absolute hypovolemia secondary to a sudden and significant extravascular blood loss, tissue injury, and, eventually, hypoxemia. These phenomena are responsible of secondary injuries such as coagulopathy, endotheliopathy, microcirculation failure, inflammation, and immune activation. Collectively, these dysfunctions lead to secondary organ failures and multi-organ failure (MOF). The development of MOF after severe trauma is one of the leading causes of morbidity and mortality, where immunological dysfunction plays a central role. Damage-associated molecular patterns induce an early and exaggerated activation of innate immunity and a suppression of adaptive immunity. Severe complications are associated with a prolonged and dysregulated immune–inflammatory state. The current challenge in the management of THS patients is preventing organ injury, which currently has no etiological treatment available. Modulating the immune response is a potential therapeutic strategy for preventing the complications of THS. Mesenchymal stromal cells (MSCs) are multipotent cells found in a large number of adult tissues and used in clinical practice as therapeutic agents for immunomodulation and tissue repair. There is growing evidence that their efficiency is mainly attributed to the secretion of a wide range of bioactive molecules and extracellular vesicles (EVs). Indeed, different experimental studies revealed that MSC-derived EVs (MSC-EVs) could modulate local and systemic deleterious immune response. Therefore, these new cell-free therapeutic products, easily stored and available immediately, represent a tremendous opportunity in the emergency context of shock. In this review, the pathophysiological environment of THS and, in particular, the crosstalk between the immune system and organ function are described. The potential therapeutic benefits of MSCs or their EVs in treating THS are discussed based on the current knowledge. Understanding the key mechanisms of immune deregulation leading to organ damage is a crucial element in order to optimize the preparation of EVs and potentiate their therapeutic effect.

Innate immunity and immunotherapy for hemorrhagic shock

“…MSCs are multipotent stem cells, which are commonly used as a clinical cell therapeutic strategy for immunomodulation and tissue repair ( 9 , 56 ). Treg cells, an immunosuppressive T cell subset, are essential for maintaining immune homeostasis and tolerance ( 57 ).…”

“…In a rat model of unilateral lung contusion followed by HS, impaired wound healing and lung structure were improved by MSCs treatment by increasing the Treg cell population ( 44 , 45 ). Cell-based therapies using MSCs or MSC-EVs are beneficial for improving neurologic outcomes and lung injury in animal models of HS ( 9 ). Moreover, in an HS-induced mild lung injury rat model, leukocyte infiltrates (CD68 + and MPO + cells) were significantly reduced in the lung after treatment with MSCs ( 46 ).…”

“…Increasing evidence has proved that the modulation of innate immune responses is a promising therapeutic strategy for preventing and treating HS-induced MOF injury and complications ( 9 ). Soon after HS insult, exposure to exogenous pathogen-associated molecular pattern molecules (PAMPs) and endogenous damaged-associated molecular pattern molecules (DAMPs) extensively activate the innate immune defense, mainly comprising type II innate lymphoid cells (ILC2), CD4 + T cells, natural killer (NK) cells, eosinophils, dendritic cells (DCs), basophils, macrophages, neutrophils, and the complement cascade ( 10 ).…”

“…The systemic parameters during HS suggest that restoration of innate immunity offers exciting and promising directions for developing novel therapeutics for HS-induced second injuries. Recently, compelling evidence has focused on the innate immune response for the monitoring and therapy of HS ( 8 , 9 , 12 , 13 ). The emerging understanding is poised to revolutionize the treatment of HS through targeted immune modulators.…”

MECHANISM OF MIR-25-3P CARRIED BY EXTRACELLULAR VESICLES DERIVED FROM PLATELET-RICH PLASMA IN IL-1β–INDUCED NUCLEUS PULPOSUS CELL DEGENERATION VIA THE SOX4/CXCR7 AXIS

“…Extracellular vesicles (EVs), a lipid membranous vesicle, can alter the effects of recipient cells through the transport of a variety of lipids, proteins, DNAs, and RNAs and thus function to cellular processes (12). An existing study reported that EVs derived from mesenchymal stromal cells can protect injured organs from traumatic hemorrhagic shock through limiting apoptosis, inflammation, and oxidative stress (13). It is noteworthy that EVs derived from multiple cells, such as fibrous cells and mesenchymal stem cells, could affect IVD degeneration (14,15).…”