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.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s12015-021-10188-w.
Highlights
The Covid19/Sars-CoV-2 pandemic has caused trillions of dollars of economic disruption
We report here that most these markers increase with normal embryonic stem cells (ESC) differentiation and increase further still with stress, and that viral resistance gene gene ontology (GO) Groups increase with normal differentiation but decrease with stress
The experimental protocol used a 72hr stimulus of ESC to normal stemness (NS) with stemness and proliferation-maintaining Leukemia inhibitory factor (LIF), normal differentiation by leukemia inhibitory factor (LIF) removal (ND), and three levels of hyperosmotic stress as a positive control of stress-forced differentiation (SFD) used in previous studies (Figure 1 [18, 21, 28])
Summary
The Covid19/Sars-CoV-2 pandemic has caused trillions of dollars of economic disruption. Key elements of a successful Covid clinical responses are testing, tracking, reducing symptoms, vaccination, and risk analysis of viral effects dependent on susceptibility. An important element of risk analysis is whether environmental toxicants, urban hormonal stresses and nutrition affect susceptibility. Stresses have been linked in a dose-dependent manner to susceptibility through infection under circumstances where host responses and symptoms play a lesser role [1]. CoV2 has evolved changes that make it more clinically dangerous than previous coronaviruses. It can infect upper respiratory throat and bronchi and create flu like symptoms or infect lungs and create pneumonia and death. Of the 7 total and 3 severe human coronaviruses (Cov, Cov, MERS), only Cov infects both the upper respiratory tract and lungs
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