Stress Decreases Host Viral Resistance and Increases Covid Susceptibility in Embryonic Stem Cells

Abstract

Graphical Abstract Stress-induced changes in viral receptor and susceptibility gene expression were measured in embryonic stem cells (ESC) and differentiated progeny. Rex1 promoter-Red Fluorescence Protein reporter ESC were tested by RNAseq after 72hr exposures to control stress hyperosmotic sorbitol under stemness culture (NS) to quantify stress-forced differentiation (SFD) transcriptomic programs. Control ESC cultured with stemness factor removal produced normal differentiation (ND). Bulk RNAseq transcriptomic analysis showed significant upregulation of two genes involved in Covid-19 cell uptake, Vimentin (VIM) and Transmembrane Serine Protease 2 (TMPRSS2). SFD increased the hepatitis A virus receptor (Havcr1) and the transplacental Herpes simplex 1 (HSV1) virus receptor (Pvrl1) compared with ESC undergoing ND. Several other coronavirus receptors, Glutamyl Aminopeptidase (ENPEP) and Dipeptidyl Peptidase 4 (DPP4) were upregulated significantly in SFD>ND. Although stressed ESC are more susceptible to infection due to increased expression of viral receptors and decreased resistance, the necessary Covid-19 receptor, angiotensin converting enzyme (ACE)2, was not expressed in our experiments. TMPRSS2, ENPEP, and DPP4 mediate Coronavirus uptake, but are also markers of extra-embryonic endoderm (XEN), which arise from ESC undergoing ND or SFD. Mouse and human ESCs differentiated to XEN increase TMPRSS2 and other Covid-19 uptake-mediating gene expression, but only some lines express ACE2. Covid-19 susceptibility appears to be genotype-specific and not ubiquitous. Of the 30 gene ontology (GO) groups for viral susceptibility, 15 underwent significant stress-forced changes. Of these, 4 GO groups mediated negative viral regulation and most genes in these increase in ND and decrease with SFD, thus suggesting that stress increases ESC viral susceptibility. Taken together, the data suggest that a control hyperosmotic stress can increase Covid-19 susceptibility and decrease viral host resistance in mouse ESC. However, this limited pilot study should be followed with studies in human ESC, tests of environmental, hormonal, and pharmaceutical stressors and direct tests for infection of stressed, cultured ESC and embryos by Covid-19. Supplementary Information The online version contains supplementary material available at 10.1007/s12015-021-10188-w.

Do selected lifestyle parameters affect the severity and symptoms of COVID-19 among elderly patients? The retrospective evaluation of individuals from the STOP-COVID registry of the PoLoCOV study

“…It has been found that the body's ability to respond to a viral infection is extremely important, which depends on various factors, including variants of the virus, implemented vaccinations, general health of the patient, individual predispositions or behavior related to lifestyle. Recognized beneficial factors for a healthy lifestyle include eating a healthy diet [16] , maintaining a healthy body weight, avoiding stress [17] , getting enough sleep [18] , and exercising regularly [19] .…”

Using Live Imaging and FUCCI Embryonic Stem Cells to Rank DevTox Risks: Adverse Growth Effects of PFOA Compared With DEP Are 26 Times Faster, 1,000 Times More Sensitive, and 13 Times Greater in Magnitude

“…We report the slowing of the cell cycle here with environmental toxic stressors, consistent with the slowing of the cell cycle using positive control hyperosmotic stress reported previously ( Slater et al, 2014 ; Li et al, 2016a ; Li et al, 2016b ; Li et al, 2019 ). Interestingly, as the cell cycle is slowed down experimentally with hyperosmotic stress, it has been reported that G1 delay is associated with increased endoderm differentiation and less neuronal differentiation ( Coronado et al, 2013 ; Pauklin and Vallier, 2013 ), and when we use stress to slow the cell cycle, with suggested G1 delay here, we have previously shown that the extra-embryonic endoderm increases ( Slater et al, 2014 ; Li et al, 2019 ; Abdulhasan et al, 2021a ; Abdulhasan et al, 2021b ) and GO groups for neuroectoderm decrease ( Abdulhasan et al, 2021b ). Thus, it will be important to test whether experimental stressors also override stemness and proliferation signals from LIF and imbalance forced differentiation similarly to hyperosmotic stress.…”

“…So, it can be concluded that hyperosmotic stress at 300 mM sorbitol or similar effects of 10–100 uM PFOA have early higher effects both on growth and stemness at higher doses and lesser effects at longer durations, as indicated by data here and in previous reports where the metabolism and stemness change over time. It will be important to determine using transcriptomic analysis if PFOA also induces changes in metabolism and stemness that are induced by hyperosmotic stress ( Abdulhasan et al, 2021a ; Abdulhasan et al, 2021b ; Abdulhasan et al, 2021c ).…”

A single cell transcriptomic fingerprint of stressed premature, imbalanced differentiation of embryonic stem cells

“…Rex1-RFP ESC were created and used previously in toxicological HTS (Abdulhasan et al, 2021a;Li et al, 2016a;Li et al, 2016b). FUCCI muESC were a kind gift from Dr. Pierre Savatier (Coronado et al, 2013).…”