Mesenchymal stromal cell-derived extracellular vesicles therapy openings new translational challenges in immunomodulating acute liver inflammation.

Inflammation plays a critical role in conditions such as acute liver failure, acute-on-chronic liver failure, and ischemia-reperfusion-induced liver injury. Various pathogenic pathways contribute to liver inflammation, involving inflammatory polarization of macrophages and Küpffer cells, neutrophil infiltration, dysregulation of T cell subsets, oxidative stress, and activation of hepatic stellate cells. While mesenchymal stromal cells (MSCs) have demonstrated beneficial properties, their clinical translation is limited by their cellular nature. However, MSC-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach for immunomodulation. MSC-EVs naturally mirror their parental cell properties, overcoming the limitations associated with the use of MSCs. In vitro and in vivo preclinical studies have demonstrated that MSC-EVs replicate the beneficial effects of MSCs in liver injury. This includes the reduction of cell death and oxidative stress, improvement of hepatocyte function, induction of immunomodulatory effects, and mitigation of cytokine storm. Nevertheless, MSC-EVs face challenges regarding the necessity of defining consistent isolation methods, optimizing MSCs culture conditions, and establishing quality control measures for EV characterization and functional assessment. By establishing standardized protocols, guidelines, and affordable cost mass production, clinicians and researchers will have a solid foundation to conduct further studies, validate the therapeutic efficacy of MSC-EVs, and ultimately pave the way for their clinical implementation in acute liver injury.

Deleterious effect of sustained neuroinflammation in pediatric traumatic brain injury.

INTRODUCTION: Despite improved management of traumatic brain injury (TBI), it still leads to lifelong sequelae and disability, particularly in children. Chronic neuroinflammation (the so-called tertiary phase), in particular, microglia/macrophage and astrocyte reactivity, is among the main mechanisms suspected of playing a role in the generation of lesions associated with TBI. The role of acute neuroinflammation is now well understood, but its persistent effect and impact on the brain, particularly during development, are not. Here, we investigated the long-term effects of pediatric TBI on the brain in a mouse model. METHODS: Pediatric TBI was induced in mice on postnatal day (P) 7 by weight-drop trauma. The time course of neuroinflammation and myelination was examined in the TBI mice. They were also assessed by magnetic resonance, functional ultrasound, and behavioral tests at P45. RESULTS: TBI induced robust neuroinflammation, characterized by acute microglia/macrophage and astrocyte reactivity. The long-term consequences of pediatric TBI studied on P45 involved localized scarring astrogliosis, persistent microgliosis associated with a specific transcriptomic signature, and a long-lasting myelination defect consisting of the loss of myelinated axons, a decreased level of myelin binding protein, and severe thinning of the corpus callosum. These results were confirmed by reduced fractional anisotropy, measured by diffusion tensor imaging, and altered inter- and intra-hemispheric connectivity, measured by functional ultrasound imaging. In addition, adolescent mice with pediatric TBI showed persistent social interaction deficits and signs of anxiety and depressive behaviors. CONCLUSIONS: We show that pediatric TBI induces tertiary neuroinflammatory processes associated with white matter lesions and altered behavior. These results support our model as a model for preclinical studies for tertiary lesions following TBI.

MRI volumetry and diffusion tensor imaging for diagnosis and follow-up of late post-traumatic injuries.

BACKGROUND: Traumatic Brain Injury (TBI) is a major cause of acquired disability and can cause devastating and progressive post-traumatic encephalopathy. TBI is a dynamic condition that continues to evolve over time. A better understanding of the pathophysiology of these late lesions is important for the development of new therapeutic strategies. OBJECTIVES: The primary objective was to compare the ability of fluid-attenuated reversion recovery (FLAIR) and diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) markers to identify participants with a Glasgow outcome scale extended (GOS-E) score of 7-8, up to 10 years after their original TBI. The secondary objective was to study the brain regionalization of DTI markers. Finally, we analyzed the evolution of late-developing brain lesions using repeated MRI images, also taken up to 10 years after the TBI. METHODS: In this retrospective study, participants were included from a cohort of people hospitalized following a severe TBI. Following their discharge, they were followed-up and clinically assessed, including a DTI-MRI scan, between 2012 and 2016. We performed a cross-sectional analysis on 97 participants at a median (IQR) of 5 years (3-6) post-TBI, and a further post-TBI longitudinal analysis over 10 years on a subpopulation (n = 17) of the cohort. RESULTS: Although the area under the curve (AUC) of FLAIR, fractional anisotropy (FA), and mean diffusivity (MD) were not significantly different, only the AUC of FA was statistically greater than 0.5. In addition, only the FA was correlated with clinical outcomes as assessed by GOS-E score (P<10-4). On the cross-sectional analysis, DTI markers allowed study post-TBI white matter lesions by region. In the longitudinal subpopulation analysis, the observed number of brain lesions increased for the first 5 years post-TBI, before stabilizing over the next 5 years. CONCLUSIONS: This study has shown for the first time that post-TBI lesions can present in a two-phase evolution. These results must be confirmed in larger studies. French Data Protection Agency (Commission nationale de l'informatique et des libertés; CNIL) study registration no: 1934708v0.

Therapeutic potentials of mesenchymal stromal cells-derived extracellular vesicles in liver failure and marginal liver graft rehabilitation: a scoping review.

Liver failure includes distinct subgroups of diseases: Acute liver failure (ALF) without preexisting cirrhosis, acute-on-chronic liver failure (ACLF) (severe form of cirrhosis associated with organ failures and excess mortality), and liver fibrosis (LF). Inflammation plays a key role in ALF, LF, and more specifically in ACLF for which we have currently no treatment other than liver transplantation (LT). The increasing incidence of marginal liver grafts and the shortage of liver grafts require us to consider strategies to increase the quantity and quality of available liver grafts. Mesenchymal stromal cells (MSCs) have shown beneficial pleiotropic properties with limited translational potential due to the pitfalls associated with their cellular nature. MSC-derived extracellular vesicles (MSC-EVs) are innovative cell-free therapeutics for immunomodulation and regenerative purposes. MSC-EVs encompass further advantages: pleiotropic effects, low immunogenicity, storage stability, good safety profile, and possibility of bioengineering. Currently, no human studies explored the impact of MSC-EVs on liver disease, but several preclinical studies highlighted their beneficial effects. In ALF and ACLF, data showed that MSC-EVs attenuate hepatic stellate cells activation, exert antioxidant, anti-inflammatory, anti-apoptosis, anti-ferroptosis properties, and promote regeneration of the liver, autophagy, and improve metabolism through mitochondrial function recovery. In LF, MSC-EVs demonstrated anti-fibrotic properties associated with liver tissue regeneration. Normothermic-machine perfusion (NMP) combined with MSC-EVs represents an attractive therapy to improve liver regeneration before LT. Our review suggests a growing interest in MSC-EVs in liver failure and gives an appealing insight into their development to rehabilitate marginal liver grafts through NMP.