Mesenchymal stromal cell extracellular vesicles improve lung development in mechanically ventilated preterm lambs.

Novel therapies are needed for bronchopulmonary dysplasia (BPD) because no effective treatment exists. Mesenchymal stromal cell extracellular vesicles (MSC-sEVs) have therapeutic efficacy in a mouse pup neonatal hyperoxia BPD model. We tested the hypothesis that MSC-sEVs will improve lung functional and structural development in mechanically ventilated preterm lambs. Preterm lambs (∼129 days; equivalent to human lung development at ∼28 wk gestation) were exposed to antenatal steroids, surfactant, caffeine, and supported by mechanical ventilation for 6-7 days. Lambs were randomized to blinded treatment with either MSC-sEVs (human bone marrow MSC-derived; 2 × 1011 particles iv; n = 8; 4 F/4 M) or vehicle control (saline iv; 4 F/4 M) at 6 and 78 h post delivery. Physiological targets were pulse oximetry O2 saturation 90-94% ([Formula: see text] 60-90 mmHg), [Formula: see text] 45-60 mmHg (pH 7.25-7.35), and tidal volume 5-7 mL/kg. MSC-sEVs-treated preterm lambs tolerated enteral feedings compared with vehicle control preterm lambs. Differences in weight patterns were statistically significant. Respiratory severity score, oxygenation index, A-a gradient, distal airspace wall thickness, and smooth muscle thickness around terminal bronchioles and pulmonary arterioles were significantly lower for the MSC-sEVs group. S/F ratio, radial alveolar count, secondary septal volume density, alveolar capillary surface density, and protein abundance of VEGF-R2 were significantly higher for the MSC-sEVs group. MSC-sEVs improved respiratory system physiology and alveolar formation in mechanically ventilated preterm lambs. MSC-sEVs may be an effective and safe therapy for appropriate functional and structural development of the lung in preterm infants who require mechanical ventilation and are at risk of developing BPD.NEW & NOTEWORTHY This study focused on potential treatment of preterm infants at risk of developing bronchopulmonary dysplasia (BPD), for which no effective treatment exists. We tested treatment of mechanically ventilated preterm lambs with human mesenchymal stromal cell extracellular vesicles (MSC-sEVs). The results show improved respiratory gas exchange and parenchymal growth of capillaries and epithelium that are necessary for alveolar formation. Our study provides new mechanistic insight into potential efficacy of MSC-sEVs for preterm infants at risk of developing BPD.

Effects of newer-generation anti-diabetics on diabetic retinopathy: a critical review.

Diabetic retinopathy (DR) is the leading etiology of blindness in the working population of the USA. Its long-term management relies on effective glycemic control. Seven anti-diabetic classes have been introduced for patients with type 2 diabetes (T2D) in the past two decades, with different glucose-lowering and cardiovascular benefits. Yet, their effects specifically on DR have not been studied in detail. A systematic review of the literature was conducted to investigate this topic, focusing on the available clinical data for T2D. Published studies were evaluated based on their level of statistical evidence, as long as they incorporated at least one endpoint or adverse event pertaining to retinal health. Fifty nine articles met our inclusion criteria and were grouped per anti-diabetic class as follows: alpha-glucosidase inhibitors (1), peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists (8), amylin analogs (1), glucagon-like peptide-1 (GLP-1) receptor agonists (28), dipeptidyl peptidase 4 (DPP-4) inhibitors (9), and sodium glucose co-transporter-2 (SGLT-2) inhibitors (9), plus one retrospective study and two meta-analyses evaluating more than one of the aforementioned anti-diabetic categories. We also reviewed publicly-announced results of trials for the recently-introduced class of twincretins. The available data indicates that most drugs in the newer anti-diabetic classes are neutral to DR progression; however, there are subclasses differences in specific drugs and T2D populations. In particular, there is evidence suggesting there may be worse diabetic macular edema with PPAR-gamma agonists, potential slight DR worsening with semaglutide (GLP-1 receptor agonist), and potential slight increase in the incidence of retinal vein occlusion in elderly and patients with advanced kidney disease receiving SGLT-2 inhibitors. All these warrant further investigation. Longer follow-up and systematic assessment of at least one DR-related endpoint are highly recommended for all future trials in the T2D field, to ultimately address this topic.

Harnessing the therapeutic potential of the stem cell secretome in neonatal diseases.

Preterm birth and intrapartum related complications account for a substantial amount of mortality and morbidity in the neonatal period despite significant advancements in neonatal-perinatal care. Currently, there is a noticeable lack of curative or preventative therapies available for any of the most common complications of prematurity including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia and retinopathy of prematurity or hypoxic-ischemic encephalopathy, the main cause of perinatal brain injury in term infants. Mesenchymal stem/stromal cell-derived therapy has been an active area of investigation for the past decade and has demonstrated encouraging results in multiple experimental models of neonatal disease. It is now widely acknowledged that mesenchymal stem/stromal cells exert their therapeutic effects via their secretome, with the principal vector identified as extracellular vesicles. This review will focus on summarizing the current literature and investigations on mesenchymal stem/stromal cell-derived extracellular vesicles as a treatment for neonatal diseases and examine the considerations to their application in the clinical setting.

Mesenchymal Stromal/Stem Cell Extracellular Vesicles and Perinatal Injury: One Formula for Many Diseases.

Over the past decades, substantial advances in neonatal medical care have increased the survival of extremely premature infants. However, there continues to be significant morbidity associated with preterm birth with common complications including bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neuronal injury such as intraventricular hemorrhage (IVH) or hypoxic ischemic encephalopathy (HIE), as well as retinopathy of prematurity (ROP). Common developmental immune and inflammatory pathways underlie the pathophysiology of such complications providing the opportunity for multisystem therapeutic approaches. To date, no single therapy has proven to be effective enough to prevent or treat the sequelae of prematurity. In the past decade mesenchymal stem/stromal cell (MSC)-based therapeutic approaches have shown promising results in numerous experimental models of neonatal diseases. It is now accepted that the therapeutic potential of MSCs is comprised of their secretome, and several studies have recognized the small extracellular vesicles (sEVs) as the paracrine vector. Herein, we review the current literature on the MSC-EVs as potential therapeutic agents in neonatal diseases and comment on the progress and challenges of their translation to the clinical setting.

Extracellular Vesicles Secreted by Corneal Myofibroblasts Promote Corneal Epithelial Cell Migration.

Corneal epithelial wound healing is a multifaceted process that encompasses cell proliferation, migration, and communication from the corneal stroma. Upon corneal injury, bidirectional crosstalk between the epithelium and stroma via extracellular vesicles (EVs) has been reported. However, the mechanisms by which the EVs from human corneal keratocytes (HCKs), fibroblasts (HCFs), and/or myofibroblasts (HCMs) exert their effects on the corneal epithelium remain unclear. In this study, HCK-, HCF-, and HCM-EVs were isolated and characterized, and human corneal epithelial (HCE) cell migration was assessed in a scratch assay following PKH26-labeled HCK-, HCF-, or HCM-EV treatment. HCE cells proliferative and apoptotic activity following EV treatment was assessed. HCF-/HCM-EVs were enriched for CD63, CD81, ITGAV, and THBS1 compared to HCK-EV. All EVs were negative for GM130 and showed minimal differences in biophysical properties. At the proteomic level, we showed HCM-EV with a log >two-fold change in CXCL6, CXCL12, MMP1, and MMP2 expression compared to HCK-/HCF-EVs; these proteins are associated with cellular movement pathways. Upon HCM-EV treatment, HCE cell migration, velocity, and proliferation were significantly increased compared to HCK-/HCF-EVs. This study concludes that the HCM-EV protein cargo influences HCE cell migration and proliferation, and understanding these elements may provide a novel therapeutic avenue for corneal wound healing.

Dissolved oxygen technologies as a novel strategy for non-healing wounds: A critical review.

Non-healing wounds are steadily becoming a global-health issue. Prolonged hypoxia propagates wound chronicity; yet, oxygenating treatments are considered inadequate to date. Dissolved oxygen (DO) in aqueous solutions introduces a novel approach to enhanced wound oxygenation, and is robustly evaluated for clinical applications. A systematic literature search was conducted, whereby experimental and clinical studies of DO technologies were categorized per engineering approach. Technical principles, methodology, endpoints and outcomes were analysed for both oxygenating and healing effects. Forty articles meeting our inclusion criteria were grouped as follows: DO solutions (17), oxygen (O2 ) dressings (9), O2 hydrogels (11) and O2 emulsions (3). All technologies improved wound oxygenation, each to a variable degree. They also achieved at least one statistically significant outcome related to wound healing, mainly in epithelialization, angiogenesis and collagen synthesis. Scarcity in clinical data and methodological variability precluded quantitative comparisons among the biotechnologies studied. DO technologies warrantee further evaluation for wound oxygenation in the clinical setting. Standardised methodologies and targeted research questions are pivotal to facilitate global integration in healthcare.