CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-κB/RelA in maintaining the homeostasis of human vascular cells

Vascular cell functionality is critical to blood vessel homeostasis. Constitutive NF-κB activation in vascular cells results in chronic vascular inflammation, leading to various cardiovascular diseases. However, how NF-κB regulates human blood vessel homeostasis remains largely elusive. Here, using CRISPR/Cas9-mediated gene editing, we generated RelA knockout human embryonic stem cells （hESCs） and differentiated them into various vascular cell derivatives to study how NF- KS modulates human vascular cells under basal and inflammatory conditions. Multi-dimensional phenotypic assessments and transcriptomic analyses revealed that RelA deficiency affected vascular cells via modulatinginflammation, survival, vasculogenesis, cell differentia- tion and extracellular matrix organization in a cell type- specific manner under basal condition, and that RelA protected vascular cells against apoptosis and modu- lated vascular inflammatory response upon tumor necrosis factor a （TNFa） stimulation. Lastly, further evaluation of gene expression patterns in IKBo knockout vascular cells demonstrated that IKBa acted largely independent of RelA signaling. Taken together, our data reveal a protective role of NF-κB/ReiA in modulating human blood vessel homeostasis and map the human vascular transcriptomic landscapes for the discovery of novel therapeutic targets.

Chemical screen identifies a geroprotective role of quercetin in premature aging

Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.

Sirtl regulates testosterone biosynthesis in Leydig cells via modulating autophagy

Dear Editor,Steroid hormones are crucial signal molecules that regulate a large number of physiological and developmental pro-cesses.Testosterone is the key steroid hormone required for the development of male characteristics and also supports the physiology of the male reproductive system(Sinclair et al.,2015).Testosterone is primarily produced by the Leydig cells residing in the testicular interstitium.The cholesterol acts as a substrate for the biosynthesis of testosterone.Since steroidogenic cells are capable of stor-ing only very ltte hormone,rapid synthesis of hormone requires the mobilization of the precursor cholesterol,chiefly stored as intracellular lipid droplets(LDs)(Danielsen et al.,2016).Leydig cells are the major sites to produce testos-terone,there are extremely active autophagy in them,and a decline in steroidogenesis has also been associated with the decline of autophagic flow.Moreover,the disruption of autophagy leads to decreased intracellular LDs,and there-fore affects testosterone synthesis in the Leydig cells(Danielsen et al..2016;Gao et al,2018).

Decreased inhibition of exosomal miRNAs on SARS-CoV-2 replication underlies poor outcomes in elderly people and diabetic patients

Elderly people and patients with comorbidities are at higher risk of COVID-19 infection,resulting in severe complications and high mortality.However,the underlying mechanisms are unclear.In this study,we investigate whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes.

Low-dose quercetin positively regulates mouse healthspan

Dear Editor,Aging is the leading risk factor for many chronic diseases,accounting for almost 60%of all deaths worldwide.How to achieve healthy aging,alleviate aging-related diseases,and extend healthspan has become a main topic of biomedical research(He et al.,2019).Geroprotective compounds,such as metformin and rapamycin,have been shown to improve both healthspan and lifespan in mice(Martin-Montalvo et al.,2013;Bitto et al.,2016),whereas nicotinamide partially improves healthspan in mice(Mitchell et al.,2018).

FOXO3-engineered human mesenchymal progenitor cells efficiently promote cardiac repair after myocardial infarction

Dear Editor,Myocardial infarction(MI)is the irreversible cardiomyocyte death resulting from prolonged oxygen deprivation due to obstructed blood supply(ischemia),leading to contractile dysfunction and cardiac remodeling.In recent decades,stem cell transplantation has been extensively investigated for the repair of injured heart in animal studies and clinical trials(Kanelidis et al.,2017;Gyongyosi et al.,2018).