human stem cell
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Biology Open ◽  
2022 ◽  
Author(s):  
Bilal M. Akhtar ◽  
Priyanka Bhatia ◽  
Shubhra Acharya ◽  
Sanjeev Sharma ◽  
Yojet Sharma ◽  
...  

Human brain development is a complex process where multiple cellular and developmental events are co-ordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS), is a X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1 that encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated, but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a “disease-in-a-dish” model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development.


2022 ◽  
Vol 29 (1) ◽  
pp. 11-35
Author(s):  
Elisa Giacomelli ◽  
Björn F. Vahsen ◽  
Elizabeth L. Calder ◽  
Yinyan Xu ◽  
Jakub Scaber ◽  
...  

Author(s):  
Ryan J. Farr ◽  
Nathan Godde ◽  
Christopher Cowled ◽  
Vinod Sundaramoorthy ◽  
Diane Green ◽  
...  

Despite being vaccine preventable, rabies (lyssavirus) still has a significant impact on global mortality, disproportionally affecting children under 15 years of age. This neurotropic virus is deft at avoiding the immune system while travelling through neurons to the brain. Until recently, research efforts into the role of non-coding RNAs in rabies pathogenicity and detection have been hampered by a lack of human in vitro neuronal models. Here, we utilized our previously described human stem cell-derived neural model to investigate the effect of lyssavirus infection on microRNA (miRNA) expression in human neural cells and their secreted exosomes. Conventional differential expression analysis identified 25 cellular and 16 exosomal miRNAs that were significantly altered (FDR adjusted P-value <0.05) in response to different lyssavirus strains. Supervised machine learning algorithms determined 6 cellular miRNAs (miR-99b-5p, miR-346, miR-5701, miR-138-2-3p, miR-651-5p, and miR-7977) were indicative of lyssavirus infection (100% accuracy), with the first four miRNAs having previously established roles in neuronal function, or panic and impulsivity-related behaviors. Another 4-miRNA signatures in exosomes (miR-25-3p, miR-26b-5p, miR-218-5p, miR-598-3p) can independently predict lyssavirus infected cells with >99% accuracy. Identification of these robust lyssavirus miRNA signatures offers further insight into neural lineage responses to infection and provides a foundation for utilizing exosome miRNAs in the development of next-generation molecular diagnostics for rabies.


Aging Cell ◽  
2021 ◽  
Author(s):  
Ali Fathi ◽  
Sakthikumar Mathivanan ◽  
Linghai Kong ◽  
Andrew J. Petersen ◽  
Cole R. K. Harder ◽  
...  

Author(s):  
Diana R. Pereira ◽  
Joana Silva-Correia ◽  
Joaquim M. Oliveira ◽  
Rui L. Reis ◽  
Abhay Pandit

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Ya Qiu ◽  
Yan Ma ◽  
Min Jiang ◽  
Sulei Li ◽  
Jibin Zhang ◽  
...  

Endotoxemia in sepsis remains a problem due to a lack of effective strategies. Our previous studies have demonstrated that melatonin (Mel) protects against ischemic heart injury and arteriosclerosis. However, its role in endotoxemia-exposed cardiomyocytes remains poorly understood. This study explored, for the first time, the protective effect of Mel on the pyroptosis of human stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to lipopolysaccharide (LPS). Our results showed that treatment with 1 μM or 10 μM Mel for 12 h significantly improved 1 μg/ml LPS-induced hiPSC-CM injuries, as reflected by drastically decreased LDH release and increased cell viability, which was accompanied by the overt induction of autophagy. Specifically, Mel profoundly alleviated LPS-induced cell pyroptosis, as evidenced by decreased propidium iodide (PI) and active caspase-1 double-positive cell rates; suppressed the expression of NLRP3, cleaved caspase-1 (activated form of caspase-1), and GSDMD-NT (functional N-terminal fragment of GSDMD) expression; and inhibited the production of the cleaved IL-1β and cleaved IL-18 cytokines. Additionally, double-membrane autophagosomes were observed in LPS-injured hiPSC-CMs treated with 1 μM or 10 μM Mel. The hiPSC-CMs treated with LPS exhibited considerably fewer acidic vesicles (as revealed by LAMP1 staining) and autophagosomes (as revealed by LC3-II staining); however, Mel reversed this outcome in a dose-dependent manner. Furthermore, coincubation with rapamycin (an autophagy activator) or 3-MA (an autophagy inhibitor) accentuated and attenuated the antipyroptotic actions of Mel, respectively. Collectively, our findings demonstrate that Mel shields hiPSC-CMs against pyroptosis during endotoxemia by activating autophagy.


2021 ◽  
Vol 105 (12S1) ◽  
pp. S13-S13
Author(s):  
Dario Gerace ◽  
Jennifer HR Kenty ◽  
Douglas A. Melton

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