Biocompatible Materials labelled with Microenvironment Responsive MRI Probes for the follow-up of Cell Transplants

Introduction: Cell encapsulation by hydrogels is intended to shield transplanted cells from the host hostile environment by preventing the infiltration of host immune cells. Cell scaffolding by solid biocompatible microparticles is intended to provide a structural support to implanted cells and to mimic the extracellular matrix, allowing cells to proliferate and/or differentiate in the desired way. We present strategies to label scaffolding biomaterials with microenvironment responsive MRI probes, for applications in the follow-up of cell transplants. Methods: Microparticles (MPs) based on PLGA/chitosan were incorporated with gadolinium fluoride nanoparticles (GdNPs), as the MRI T1-contrast agent. The system is designed such to release Gd-NPs in the extracellular matrix (ECM), thus activating MRI contrast, unless MPs are attacked by the immune system (Foreign Body Response, FBR). To proof the concept, PLGA-based MPs were seeded with hMSCs and implanted into either immunocompetent or immunocompromised mice, and the transplants were followed-up by MRI for three weeks. Ex-vivo histologic assessment was carried out at the end of the follow-up. Results/Discussion: Immunocompetent mice showed poor activation, if any, of MRI contrast within the cell graft. Immunocompromised mice, on the other hand, showed a progressive activation of MRI contrast. Ex-vivo histology showed extensive FBR directed against microparticles in immunocompetent mice, with some surviving hMSCs in the ECM but not on the scaffold surface. No significant FBR was detected in immunocompromised mice, and hMSCs were still adhering to the scaffolds. Conclusions: The proposed system is able to assess whether or not cell grafts are subjected to innate immune response, an event that is likely correlated to the loss of transplanted cells

Increased Placental Anti‐Oxidant Response in Asymptomatic and Symptomatic COVID‐19 Third‐Trimester Pregnancies

Despite Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) -induced Oxidative Stress (OxS) being well documented in different organs, the molecular pathways underlying placental OxS in late-pregnancy women with SARS-CoV-2 infection are poorly understood. Herein, we performed an observational study to determine whether placentae of women testing positive for SARS-CoV-2 during the third trimester of pregnancy showed redox-related alterations involving Catalase (CAT) and Superoxide Dismutase (SOD) antioxidant enzymes as well as placenta morphological anomalies relative to a cohort of healthy pregnant women. Next, we evaluated if placental redox-related alterations and mitochondria pathological changes were correlated with the presence of maternal symptoms. We observed ultrastructural alterations of placental mitochondria accompanied by increased levels of oxidative stress markers Thiobarbituric Acid Reactive Substances (TBARS) and Hypoxia Inducible Factor-1 α (HIF-1α) in SARS-CoV-2 women during the third trimester of pregnancy. Importantly, we found an increase in placental CAT and SOD antioxidant enzymes accompanied by physiological neonatal outcomes. Our findings strongly suggest a placenta-mediated OxS inhibition in response to SARS-CoV-2 infection, thus contrasting the cytotoxic profile caused by Coronavirus Disease 2019 (COVID-19)

Protective Effects of Pyridoxamine Supplementation in the Early Stages of Diet-Induced Kidney Dysfunction

Pyridoxamine, a structural analog of vitamin B6 that exerts antiglycative effects, has been proposed as supplementary approach in patients with initial diabetic nephropathy. However, the molecular mechanism(s) underlying its protective role has been so far slightly examined. C57Bl/6J mice were fed with a standard diet (SD) or a diet enriched in fat and fructose (HD) for 12 weeks. After 3 weeks, two subgroups of SD and HD mice started pyridoxamine supplementation (150 mg/kg/day) in the drinking water. HD fed mice showed increased body weight and impaired glucose tolerance, whereas pyridoxamine administration significantly improved insulin sensitivity, but not body weight, and reduced diet-induced increase in serum creatinine and urine albumin. Kidney morphology of HD fed mice showed strong vacuolar degeneration and loss of tubule brush border, associated with a drastic increase in both advanced glycation end products (AGEs) and AGEs receptor (RAGE). These effects were significantly counteracted by pyridoxamine, with consequent reduction of the diet-induced overactivation of NF-kB and Rho/ROCK pathways. Overall, the present study demonstrates for the first time that the administration of the antiglycative compound pyridoxamine can reduce the early stages of diet-dependent kidney injury and dysfunction by interfering at many levels with the profibrotic signaling and inflammatory cascades