Extracellular vesicle (EV) secretion is an important mechanism used by cells to release biomolecules. A common necroptosis effector—mixed lineage kinase domain like (MLKL)—was recently found to participate in the biogenesis of small and large EVs independent of its function in necroptosis. The objective of the current study is to gain mechanistic insights into EV biogenesis during necroptosis. Assessing EV number by nanoparticle tracking analysis revealed an increased number of EVs released during necroptosis. To evaluate the nature of such vesicles, we performed a newly adapted, highly sensitive mass spectrometry‐based proteomics on EVs released by healthy or necroptotic cells. Compared to EVs released by healthy cells, EVs released during necroptosis contained a markedly higher number of unique proteins. Receptor interacting protein kinase‐3 (RIPK3) and MLKL were among the proteins enriched in EVs released during necroptosis. Further, mouse embryonic fibroblasts (MEFs) derived from mice deficient of Rab27a and Rab27b showed diminished basal EV release but responded to necroptosis with enhanced EV biogenesis as the wildtype MEFs. In contrast, necroptosis‐associated EVs were sensitive to Ca2+ depletion or lysosomal disruption. Neither treatment affected the RIPK3‐mediated MLKL phosphorylation. An unbiased screen using RIPK3 immunoprecipitation‐mass spectrometry on necroptotic EVs led to the identification of Rab11b in RIPK3 immune‐complexes. Our data suggests that necroptosis switches EV biogenesis from a Rab27a/b dependent mechanism to a lysosomal mediated mechanism.
Abdominal aortic aneurysm (AAA), defined as a focal dilation of the abdominal aorta beyond 50% of its normal diameter, is a common and potentially life-threatening vascular disease. The molecular and cellular mechanisms underlying AAA pathogenesis remain unclear. Healthy endothelial cells (ECs) play a critical role in maintaining vascular homeostasis by regulating vascular tone and maintaining an anti-inflammatory, anti-thrombotic local environment. Increasing evidence indicates that endothelial dysfunction is an early pathologic event in AAA formation, contributing to both oxidative stress and inflammation in the degenerating arterial wall. Recent studies utilizing single-cell RNA sequencing revealed heterogeneous EC sub-populations, as determined by their transcriptional profiles, in aortic aneurysm tissue. This review summarizes recent findings, including clinical evidence of endothelial dysfunction in AAA, the impact of biomechanical stress on EC in AAA, the role of endothelial nitric oxide synthase (eNOS) uncoupling in AAA, and EC heterogeneity in AAA. These studies help to improve our understanding of AAA pathogenesis and ultimately may lead to the generation of EC-targeted therapeutics to treat or prevent this deadly disease.
Flexible implantable medical devices (IMDs) are an emerging technology that may substantially improve the disease treatment efficacy and quality of life of patients. While many advancements have been achieved in IMDs, the constantly straining application conditions impose extra requirements for the packaging material, which needs to retain both high stretchability and high water resistivity under dynamic strains in a physiological environment. This work reports a polyisobutylene (PIB) blendbased elastomer that simultaneously offers a tissue-like elastic modulus and excellent water resistivity under dynamic strains. The PIB blend is a homogeneous mixture of two types of PIB molecules with distinct molecular weights. The blend achieved an optimal Young's modulus of 62 kPa, matching those of soft biological tissues. The PIB blend film also exhibited an extremely low water permittivity of 1.6−2.9 g m −2 day −1 , from unstrained to 50% strain states. The combination of high flexibility and dynamic water resistivity was tested using triboelectric nanogenerators (TENGs). The PIB blendpackaged TENG was able to stably operate in water for 2 weeks, substantially surpassing the protection offered by Ecoflex. This work offered a promising material solution for packaging flexible IMDs to achieve stable performance in a strained physiological environment.
Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.
Introduction: Injection of induced pluripotent stem cell-derived cardiomyocytes has been reported as a promising approach to regenerate loss myocardium and restore heart function after ischemic injury. However, immaturity of the transplanted cardiomyocytes and their poor survival rates caused by limited blood supply remain as major hurdles for clinical translation. Hypothesis: We tested the hypothesis that co-culture of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) with hiPSC-derived endothelial cells (ECs) promotes CM maturation in vitro, and that co-transplantation of both hiPSC-CMs and hiPSC-ECs facilitates hiPSC-CM muscularization in myocardial ischemic injured mice and non-human primates. Methods and Results: We examined the therapeutic effect of co-transplantation of hiPSC-CMs and hiPSC-ECs in NOD-SCID mice undergoing myocardial infarction (N = 14 / group). Mice receiving co-transplantation had an improvement in ejection fraction compared to control (4.2 ± 1.2 % vs -8.4 ± 0.9 %, P < 0.0001), and even those receiving high-dose (-0.3 ± 0.9 %, P = 0.052) and low-dose (-2.4 ± 1.1 %, P = 0.001) hiPSC-CMs alone treatment. Moreover, less arrhythmic events were observed in co-transplantation using three-lead electrogram. To be more clinically relevant, we first showed in healthy non-human primates (N = 4) that hiPSC-CM engraftment, maturation, and integration was achieved when co-transplanted with hiPSC-ECs. Furthermore, we then examined the therapeutic effect of co-transplantation of hiPSC-CMs and hiPSC-ECs in rhesus macaques undergoing ischemia-reperfusion surgery (N = 3 / group). Consistent with the mouse model, co-transplantation in rhesus macaques significantly improved the ejection fraction (10 ± 1.3 % vs -1.8 ± 2.2 %, P = 0.010), accompanied by a reduced infarct size compared to control (16 ± 1.1 % vs 23 ± 3.3 %, P = 0.091). Conclusions: This study demonstrates the beneficial effects of co-transplantation of hiPSC-CMs with hiPSC-ECs, promoting hiPSC-CM maturation, enhancing neovascularization, and improving cardiac function in both mouse and non-human primate hearts. Delivery of this combined cell therapy holds promise for future clinical translation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.