Wharton's Jelly Mesenchymal Stem Cell-Derived Extracellular Vesicles Reduce SARS-CoV2-Induced Inflammatory Cytokines Under High Glucose and Uremic Toxin Conditions

Khánh, Vương Cát; Fukushige, Mizuho; Chang, Yun Hsuan; Hoang, Ngo Nhat; Yamashita, Toshiharu; Obata‐Yasuoka, Mana; Hamada, Hiromi; Osaka, Motoo; Hiramatsu, Yuji; Onodera, Osamu

doi:10.1089/scd.2021.0065

Cited by 21 publications

(21 citation statements)

References 54 publications

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“…We showed that HG levels enhanced ACE2 mRNA and protein expression levels in Calu-3 cells via GLUT1 in a dose-and time-dependent manner. Vuong Cat Khanh et al already showed ACE2 expression in Calu-3 cells were enhanced under high glucose concentration [16]., and we found that GLUT1 is the receptor to enhance expression of ACE2. SARS-CoV-2 enters host cells using viral surface transmembrane spike (S) glycoprotein [17].…”

Section: Discussionsupporting

confidence: 62%

High D-glucose levels induce ACE2 expression via GLUT1 in human airway epithelial cell line Calu-3

Wakabayashi

Nakayama

Yamamoto

et al. 2022

BMC Mol and Cell Biol

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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptors. ACE2 is expressed on human airway epithelial cells. Increased ACE2 expression may be associated with potentially high risk of COVID-19. However, the factors responsible for the regulation of ACE2 expression in human airway epithelial cells are unknown. Furthermore, hyperglycemia is a risk factor for poor disease prognosis. Results In this study, we investigated the effects of D-glucose on ACE2 mRNA and protein expressions in Calu-3 bronchial submucosal cells. The cells were cultured in minimal essential medium containing different D-glucose concentrations. After 48 and 72 h of high D-glucose (1000 mg/dL) treatment, ACE2 mRNA expressions were significantly increased. ACE2 protein expressions were significantly increased after 24 h of high D-glucose treatment. ACE2 mRNA expression was enhanced by a D-glucose concentration of 550 mg/dL or more after 72 h of treatment. In addition, we investigated the role of glucose transporters (GLUTs) in Calu-3 cells. ACE2 mRNA and protein expressions were suppressed by the GLUT1 inhibitor BAY-876 in high D-glucose-treated Calu-3 cells. GLUT-1 siRNA was also used and ACE2 mRNA expressions were suppressed in high D-glucose-treated Calu-3 cells with GLUT-1 knockdown. Conclusions This is the first report indicating that high D-glucose levels induced ACE2 expression via GLUT1 in bronchial submucosal cells in vitro. As hyperglycemia can be treated appropriately, these findings could help reduce the risk of worsening of coronavirus disease 2019.

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Section: Discussionsupporting

confidence: 62%

High D-glucose levels induce ACE2 expression via GLUT1 in human airway epithelial cell line Calu-3

Wakabayashi

Nakayama

Yamamoto

et al. 2022

BMC Mol and Cell Biol

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“…In addition to n6-acetyl-l-lysine, data showed significantly upregulated levels of the protein-bound uremic retention solute p-cresol ( p < 0.05) in COVID-19 overweight-obese patients when compared to COVID-19 lean patients ( Figure 3B ). P-cresol is known to associate with increased admissions of hospitalizations due to infections ( 36 ). Moreover, its high levels is usually correlated with chronic inflammation and cardiovascular diseases ( 37 ).…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, findings from in vitro work with human lung adenocarcinoma epithelial cells (Calu-3 cells) also indicates that uremic toxin p-cresol contributes to the induction of cytokine storm in response to SARS-CoV. Culturing Calu-3 cells with p-cresol induced responses that exhibited enhanced expression and secretion of the proinflammatory tumor necrosis factor (TNF-α), Interleukins (IL-6 and IL-1β), and interferon gamma (IFNγ) cytokines ( 36 ). This suggests that our identified metabolic signatures, N6-acetyl L-Lysine and p-Cresol, are potentially involved in inducing cytokine storm.…”

Section: Discussionmentioning

confidence: 99%

“…p-Cresol has been evidenced to inhibit macrophage function and leukocyte migration involved in cytokine-stimulated cells ( 46 ). Moreover, p-cresol has shown to significantly upregulate ACE2 and TMPRSS2, the receptors for SARS-CoV-2, which reflects more viral entry into the host cell ( 36 ). Overall, this suggests that n6-acetyl-l-lysine and p-cresol are two key metabolites that may play crucial roles in the COVID-19 pathogenesis, where obesity could be a triggering factor.…”

Section: Discussionmentioning

confidence: 99%

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N6-Acetyl-L-Lysine and p-Cresol as Key Metabolites in the Pathogenesis of COVID-19 in Obese Patients

et al. 2022

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Despite the growing number of the vaccinated population, COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global health burden. Obesity, a metabolic syndrome affecting one-third of the population, has proven to be a major risk factor for COVID-19 severe complications. Several studies have identified metabolic signatures and disrupted metabolic pathways associated with COVID-19, however there are no reports evaluating the role of obesity in the COVID-19 metabolic regulation. In this study we highlight the involvement of obesity metabolically in affecting SARS-CoV-2 infection and the consequent health complications, mainly cardiovascular disease. We measured one hundred and forty-four (144) metabolites using ultra high-performance liquid chromatography-quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS) to identify metabolic changes in response to SARS-CoV-2 infection, in lean and obese COVID-19 positive (n=82) and COVID-19 negative (n=24) patients. The identified metabolites are found to be mainly correlating with glucose, energy and steroid metabolisms. Further data analysis indicated twelve (12) significantly yet differentially abundant metabolites associated with viral infection and health complications, in COVID-19 obese patients. Two of the detected metabolites, n6-acetyl-l-lysine and p-cresol, are detected only among the COVID-19 cohort, exhibiting significantly higher levels in COVID-19 obese patients when compared to COVID-19 lean patients. These metabolites have important roles in viral entry and could explain the increased susceptibility of obese patients. On the same note, a set of six metabolites associated with antiviral and anti-inflammatory functions displayed significantly lower abundance in COVID-19 obese patients. In conclusion, this report highlights the plasma metabolome of COVID-19 obese patients as a metabolic feature and signature to help improve clinical outcomes. We propose n6-acetyl-l-lysine and p-cresol as potential metabolic markers which warrant further investigations to better understand their involvement in different metabolic pathways in COVID-19.

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“…Both studies were completed without any adverse events or safety concerns. Recently, Khanh et al reported that the Wharton's jelly MSC-derived EVs showed significant reduction in nuclear NF-κB p65 and suppression of the cytokine storm in COVID-19 patients suffering from diabetes mellitus or renal disease [ 104 ].…”

Section: Stem Cell-derived Extracellular Vesicles In Covid-19 and Acu...mentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Management of COVID19-Associated Lung Injury: A Review on Publications, Clinical Trials and Patent Landscape

Krishnan

Muthusamy

Fernandez

et al. 2022

Tissue Eng Regen Med

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The unprecedented COVID-19 pandemic situation forced the scientific community to explore all the possibilities from various fields, and so far we have seen a lot of surprises, eureka moments and disappointments. One of the approaches from the cellular therapists was exploiting the immunomodulatory and regenerative potential of mesenchymal stromal cells (MSCs), more so of MSC-derived extracellular vesicles (EVs)—particularly exosomes, in order to alleviate the cytokine storm and regenerate the damaged lung tissues. Unlike MSCs, the EVs are easier to store, deliver, and are previously shown to be as effective as MSCs, yet less immunogenic. These features attracted the attention of many and thus led to a tremendous increase in publications, clinical trials and patent applications. This review presents the current landscape of the field and highlights some interesting findings on MSC-derived EVs in the context of COVID-19, including in silico, in vitro , in vivo and case reports. The data strongly suggests the potential of MSC-derived EVs as a therapeutic regime for the management of acute lung injury and associated complications in COVID-19 and beyond. Graphical abstract

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Wharton's Jelly Mesenchymal Stem Cell-Derived Extracellular Vesicles Reduce SARS-CoV2-Induced Inflammatory Cytokines Under High Glucose and Uremic Toxin Conditions

Cited by 21 publications

References 54 publications

High D-glucose levels induce ACE2 expression via GLUT1 in human airway epithelial cell line Calu-3

High D-glucose levels induce ACE2 expression via GLUT1 in human airway epithelial cell line Calu-3

N6-Acetyl-L-Lysine and p-Cresol as Key Metabolites in the Pathogenesis of COVID-19 in Obese Patients

Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Management of COVID19-Associated Lung Injury: A Review on Publications, Clinical Trials and Patent Landscape

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