Fibroblast Growth Factor 7 Enhances Expression Of ACE2 In Pancreatic Islet Cells, Aggravating SARS-CoV-2 Infection
Nikhil Prasad Fact checked by:Thailand Medical News Team Apr 28, 2024 1 week, 6 days, 12 hours, 49 minutes ago
COVID-19 News: The ongoing battle against COVID-19 has highlighted the critical role of the angiotensin-converting enzyme 2 (ACE2) as the primary receptor for SARS-CoV-2, the virus responsible for the pandemic. Tissues with higher ACE2 expression levels are more vulnerable to SARS-CoV-2 infection, making ACE2 regulation a key target in combating the virus. Various strategies, including the use of small molecules and FDA-approved drugs, have been explored to modulate ACE2 expression and reduce susceptibility to SARS-CoV-2. One promising avenue is the investigation of fibroblast growth factors (FGFs) and their potential role in ACE2 regulation.
FGF7 enhances the expression of ACE2 in human islet organoids aggravating SARS-CoV-2 infection
Dynamic expression of ACE2 during the differentiation of human islet organoids from hESCs. a Schematic diagram outlining the differentiation protocol. The cells from the ES to S5 stages were subjected to 2D culture and the cells in S6 and S7 were suspended and 3D aggregated at the first day of S6. ES embryonic stem cells, DE definitive endoderm, PGT primitive gut tube, PF posterior foregut, PE pancreatic endocrine, EP endocrine progenitor. b Dynamic changes in ACE2 mRNA expression relative to ES from S1 to S7 relative to that in the ES stage. The dashed line indicates ACE2 mRNA expression in ES cells, which was set as 1. c Western blot analysis of ACE2 protein levels relative to that of β-actin from S1 to S7. d Quantification of the ACE2 protein level relative to that of β-actin from S1 to S7. The dashed line represents the intensity of β-actin, which was set to 1. e Immunofluorescence (IF) staining of differentiated cells from each stage for ACE2 (green) and stage-specific markers (red or white, S1: SOX17; S2: FOXA2; S3: PDX1; S4: PDX1 and NKX6.1; S5: PDX1 and NKX6.1). The white arrowheads represent the colocalization of ACE2 with stage-specific markers. The image at the bottom provides an enlarged perspective of the enclosed region within the dashed box. f Cryosections of islet organoids at S6D5 and S7D14 were subjected to IF staining for ACE2 and endocrine markers (GCG, INS, and SST). The image in the top-right corner of the picture represents an enlarged view of the region enclosed within the dashed box. g Quantification of (f) showing the percentage (%) of ACE2+ cells among GCG+, INS+, and SST+ cells in islet organoids. h IF staining of ACE2 in purified α (GCG+), purified β (INS+), and δ (SST+) cells from S7D14 islet organoids. The image on the right-hand side represents an enlarged view of the region enclosed within the dashed box. i Quantification of (h) revealing the percentages of ACE2+ cells among GCG+ cells, INS+ cells and SST+ cells. j Western blot image and quantification of ACE2 protein levels relative to β-actin in purified α cells, purified β cells and α−β− cells (the remaining cells after sequentially sorting α and β cells) from S7D14 islet organoids. Images are from one representative experiment from 3 to 5 independent experiments.
This
COVID-19
News report covers a recent study by researchers from Guangzhou Medical University-China, Guangzhou National Laboratory-China, The First Affiliated Hospital of Guangzhou Medical University-China and Wuhan Jinyintan Hospital-China that found that Fibroblast Growth Factor 7 (FGF7) enhances expression of ACE2 in pancreatic islet cells, aggravating SARS-CoV-2 infection.
The Significance of Fibroblast Growth Factors in ACE2 Regulation
FGFs are known for their diverse roles in cellular processes such as proliferation, inflammation, and tissue repair. Recent studies have suggested a link between FGFs and ACE2, indicating that FGFs may serve as regulatory factors for ACE2 expression. Among the FGF family, fibroblast growth factor 7 (FGF7) stands out due to its crucial role in pancreatic development, regeneration, and islet survival. However, the specific relationship between FGF7 and ACE2 in the context of COVID-19 remains largely unexplored, especially concerning its impact on pancreatic islet cells and insulin secretion.
The Intersection of COVID-19, Diabetes, and ACE2
COVID-19 has been associated with an increased risk of new-onset diabetes, highlighting the complex interplay between the virus, ACE2, and metabolic function. Initially, concerns arose regarding the use of certain anti-diabetic drugs that upregulate ACE2 expression, potentially exacerbating COVID-19 symptoms in diabetic patients. However, retrospective clinical studies have not substantiated these concerns, and ACE2's role in insulin secretion and metabolic regulation warrants further investigation, particularly in human islets.
Methodology and Findings: Unraveling the FGF7-ACE2 Connection
In this study that is covered in this
COVID-19 News report, the researchers employed human embryonic stem cell (hESC)-derived islet organoids, animal models, and clinical data from COVID-19 patients to elucidate the impact of FGF7 on ACE2 expression within pancreatic islet cells.
The study findings revealed a dynamic relationship between FGF7 and ACE2:
-Dynamic Expression of ACE2: The study team observed fluctuating levels of ACE2 during islet development, with a predominant expression in β cells compared to α and δ cells.
-FGF7 Regulation: FGF7 was found to regulate ACE2 expression primarily through the FGFR2 receptor in pancreatic progenitor cells, particularly enhancing ACE2 levels in β cells within islet organoids.
-Functional Implications: The upregulation of ACE2 by FGF7 had functional consequences, impacting insulin secretion and the susceptibility of β cells to SARS-CoV-2 infection.
-Clinical Correlations: Retrospective clinical data indicated elevated FGF7 levels in diabetic patients with severe COVID-19 symptoms, suggesting a potential biomarker for disease severity.
-In Vivo Experiments: Animal studies revealed an increase in pancreatic FGF7 levels during SARS-CoV-2 infection, correlating with reduced insulin concentrations and highlighting the specific impact on pancreatic function.
Discussion: Implications and Future Directions
The findings from our study shed light on the intricate interplay between FGF7, ACE2, and SARS-CoV-2 infection in pancreatic islet cells. By elucidating the FGF7-FGFR2-ACE2 pathway, we propose a potential regulatory strategy for ACE2 expression to mitigate viral infection and preserve pancreatic function, especially in diabetic individuals facing COVID-19.
Conclusion: A Path Forward in ACE2 Regulation
In conclusion, the discovery of FGF7's role in enhancing ACE2 expression in pancreatic islet cells opens avenues for targeted interventions in combating COVID-19, particularly in populations with underlying metabolic conditions. Further research into the precise mechanisms and downstream pathways involved in FGF7-ACE2 regulation is warranted to develop effective therapeutic strategies and improve outcomes for COVID-19 patients, especially those with comorbidities such as diabetes.
The study findings were published in the peer reviewed journal: Signal Transduction and Targeted Therapy (Nature-Springer).
https://www.nature.com/articles/s41392-024-01790-8
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