Wnt3a‐Loaded Extracellular Vesicles Promote Alveolar Epithelial Regeneration after Lung Injury

Abstract Compromised regeneration resulting from the deactivation of Wnt/β‐catenin signaling contributes to the progression of chronic obstructive pulmonary disease (COPD) with limited therapeutic options. Extracellular cytokine‐induced Wnt‐based signaling provides an alternative option for COPD treatment. However, the hydrophobic nature of Wnt proteins limits their purification and use. This study devises a strategy to deliver the membrane‐bound wingless‐type MMTV integration site family, member 3A (Wnt3a) over a long distance by anchoring it to the surface of extracellular vesicles (EVs). The newly engineered Wnt3aWG EVs are generated by co‐expressing Wnt3a with two genes encoding the membrane protein, WLS, and an engineered glypican, GPC6ΔGPI‐C1C2. The bioactivity of Wnt3aWG EVs is validated using a TOPFlash assay and a mesoderm differentiation model of human pluripotent stem cells. Wnt3aWG EVs activate Wnt signaling and promote cell growth following human alveolar epithelial cell injury. In an elastase‐induced emphysema model, impaired pulmonary function and enlarged airspace are greatly restored by the intravenous delivery of Wnt3aWG EVs. Single‐cell RNA sequencing–based analyses further highlight that Wnt3aWG EV‐activated regenerative programs are responsible for its beneficial effects. These findings suggest that EV‐based Wnt3a delivery represents a novel therapeutic strategy for lung repair and regeneration after injury

Decline of SARS-CoV-2 specific IgG, IgM and IgA in convalescent COVID-19 patients within 100 days after hospital discharge

AbstractMonitoring the levels of SARS-CoV-2 specific antibodies such as IgG, M and A in COVID-19 patient is an alternative method for diagnosing SARS-CoV-2 infection and an simple way to monitor immune responses in convalescent patients and after vaccination. Here, we assessed the levels of SARS-CoV-2 RBD specific antibodies in twenty-seven COVID-19 convalescent patients over 28–99 days after hospital discharge. Almost all patient who had severe or moderate COVID-19 symptoms and a high-level of IgG during the hospitalization showed a significant reduction at revisit. The remaining patients who had a low-level IgG during hospitalization stayed low at revisit. As expected, IgM levels in almost all convalescent patients reduced significantly or stayed low at revisit. The RBD-specific IgA levels were also reduced significantly at revisit. We also attempted to estimate decline rates of virus-specific antibodies using a previously established exponential decay model of antibody kinetics after infection. The predicted days when convalescent patients’ RBD-specific IgG reaches to an undetectable level are approximately 273 days after hospital discharge, while the predicted decay times are 150 days and 108 days for IgM and IgA, respectively. This investigation and report will aid current and future studies to develope SARS-CoV-2 vaccines that are potent and long-lasting.</jats:p

An Optimized Human Erythroblast Differentiation System Reveals Cholesterol‐Dependency of Robust Production of Cultured Red Blood Cells Ex Vivo

Abstract The generation of cultured red blood cells (cRBCs) ex vivo represents a potentially unlimited source for RBC transfusion and other cell therapies. Human cRBCs can be generated from the terminal differentiation of proliferating erythroblasts derived from hematopoietic stem/progenitor cells or erythroid precursors in peripheral blood mononuclear cells. Efficient differentiation and maturation into cRBCs highly depend on replenishing human plasma, which exhibits variable potency across donors or batches and complicates the consistent cRBC production required for clinical translation. Hence, the role of human plasma in erythroblast terminal maturation is investigated and uncovered that 1) a newly developed cell culture basal medium mimicking the metabolic profile of human plasma enhances cell growth and increases cRBC yield upon erythroblast terminal differentiation and 2) LDL‐carried cholesterol, as a substitute for human plasma, is sufficient to support erythroid survival and terminal differentiation ex vivo. Consequently, a chemically‐defined optimized medium (COM) is developed, enabling robust generation of cRBCs from erythroblasts of multiple origins, with improved enucleation efficiency and higher reticulocyte yield, without the need for supplementing human plasma or serum. In addition, the results reveal the crucial role of lipid metabolism during human terminal erythropoiesis

Collaborative design of polarization and antiferrodistortion configurations in high energy capacitive relaxor ferroelectrics

Abstract Lead-free relaxor ferroelectrics have been regarded as superior candidates for dielectric energy storage applications. Nonetheless, the degradation of energy storage performance resulted from the trade-off between high polarization and low hysteresis in RFEs under superhigh electric fields has become a bottleneck. Here, a chemical framework is established based on NaNbO3-based RFEs, bridging atomic-scale structural control to realize excellent energy storage performance. The framework design leads to unique local lattice distortion with both inhomogeneous polarization and antiferrodistortion configurations, including locally disordered polarization distribution, continuous polarization deflection and the co-existence of ordered and disordered oxygen octahedral tilts, as confirmed by phase-field simulation and scanning transmission electron microscopy. As a result, negligible polarization switching hysteresis as well as the large and delayed saturated polarization simultaneously contribute to the excellent energy storage performance. For instance, two NaNbO3-based RFEs with different compositions show ultrahigh recoverable energy densities of 16.48 and 20.08 J cm-3, respectively, as well as near-zero energy loss (η ~ 90.38% and 95.09%). This work presents new avenues toward designing high-performance lead-free RFEs