Abstract
COVID-19 and infectious diseases have been included in strategic development goals (SDG) of United Nations (UN). The SARS-CoV-2 pandemic has unveiled complex pathophysiological mechanisms underpinning COVID-19, notably inducing a systemic acquired vascular hemopathy characterized by endothelial dysfunction and intussusceptive angiogenesis, a rapid vascular remodeling process identified as a hallmark in severe COVID-19 cases affecting pulmonary and cardiac tissues. Stem cell migration have been proposed as significant regulators of this neoangiogenic process. In a monocentric cross-sectional study, through spectral flow cytometry analysis of peripheral blood mononuclear cells, we identified a distinct stem cell subpopulation mobilized in critical COVID-19. Indeed, by an unsupervised analysis generating a UMAP representation we highlighted eleven different clusters in critical and non-critical COVID-19 patients. Only one cluster was significantly associated to critical COVID-19 compared to non-critical patients. This cluster expressed the markers: CD45dim, CD34+, CD117+, CD147+, and CD143+, and were negative for CD133. Higher level of expression of hemangioblast markers CD143 were found in critical COVID-19 patients. This population, indicative of hemangioblast-like cells, suggests a key role in COVID-19-related neoangiogenesis, potentially driving the severe vascular complications observed. Our findings underscore the need for further investigation into the contributions of adult stem cells in COVID-19 pathology, offering new insights into therapeutic targets and interventions.
Graphical Abstract
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Raw data are available upon request.
References
Debuc, B., & Smadja, D. M. (2021). Is COVID-19 a New Hematologic Disease? Stem Cell Rev Rep, 17(1), 4–8.
Smadja, D. M., Mentzer, S. J., Fontenay, M., Laffan, M. A., Ackermann, M., Helms, J., et al. (2021). COVID-19 is a systemic vascular hemopathy: Insight for mechanistic and clinical aspects. Angiogenesis, 24(4), 755–788.
Smadja, D. M., Jannot, A. S., Philippe, A., Lu, E., Rancic, J., Sanchez, O. (2023). Circulating Von Willebrand factor: A consistent biomarker predicting in-hospital mortality across different waves of the COVID-19 pandemic. Angiogenesis. .
Ackermann, M., Verleden, S. E., Kuehnel, M., Haverich, A., Welte, T., Laenger, F., et al. (2020). Pulmonary vascular endothelialitis, thrombosis, and Angiogenesis in Covid-19. New England Journal of Medicine, 383(2), 120–128.
Werlein, C., Ackermann, M., Stark, H., Shah, H. R., Tzankov, A., Haslbauer, J. D. (2022). Inflammation and vascular remodeling in COVID-19 hearts. Angiogenesis. ;1–16.
Djonov, V., Schmid, M., Tschanz, S. A., & Burri, P. H. (2000). Intussusceptive Angiogenesis: Its role in embryonic vascular network formation. Circulation Research, 86(3), 286–292.
Baum, O., Suter, F., Gerber, B., Tschanz, S. A., Buergy, R., Blank, F., et al. (2010). VEGF-A promotes intussusceptive angiogenesis in the developing chicken chorioallantoic membrane. Microcirculation (New York, N.Y. : 1994), 17(6), 447–457.
Philippe, A., Günther, S., Rancic, J., Cavagna, P., Renaud, B., Gendron, N. (2023). VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients. Angiogenesis. .
Guerin, C. L., Guyonnet, L., Goudot, G., Revets, D., Konstantinou, M., Chipont, A., et al. (2021). Multidimensional Proteomic Approach of endothelial progenitors demonstrate expression of KDR restricted to CD19 cells. Stem Cell Rev Rep, 17(2), 639–651.
Philippe, A., Chocron, R., Gendron, N., Bory, O., Beauvais, A., Peron, N., et al. (2021). Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality. Angiogenesis, 24(3), 505–517.
Smadja, D. M., Philippe, A., Ferreira, E. V. M., Oliveira, R. K. F., McCabe, C., & Zhao, L. (2023). CD147 plasma levels in Hospitalised patients with Covid-19 Pneumonia Predict Illness Severity and In-Hospital mortality. Stem Cell Rev Rep. .
Ulrich, H., & Pillat, M. M. (2020). CD147 as a target for COVID-19 treatment: Suggested effects of Azithromycin and Stem Cell Engagement. Stem Cell Rev Rep, 16(3), 434–440.
Geng, J., Chen, L., Yuan, Y., Wang, K., Wang, Y., Qin, C., et al. (2021). CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma. Sig Transduct Target Ther, 6(1), 347.
Zambidis, E. T., Park, T. S., Yu, W., Tam, A., Levine, M., Yuan, X., et al. (2008). Expression of angiotensin-converting enzyme (CD143) identifies and regulates primitive hemangioblasts derived from human pluripotent stem cells. Blood, 112(9), 3601–3614.
Rodgers, K. E., & Dizerega, G. S. (2013). Contribution of the local RAS to hematopoietic function: A Novel Therapeutic Target. Front Endocrinol (Lausanne), 4, 157.
Slukvin, I. I. (2009). Renin-angiotensin system and hemangioblast development from human embryonic stem cells. Expert Rev Hematol, 2(2), 137–143.
Becht, E., McInnes, L., Healy, J., Dutertre, C. A., Kwok, I. W. H., Ng, L. G. (2018). Dimensionality reduction for visualizing single-cell data using UMAP. Nature Biotechnology. .
Aragon, J. W., & Hirschi, K. K. (2022). Endothelial cell differentiation and hemogenic specification. Cold Spring Harb Perspect Med, 12(7), a041164.
Ratajczak, M. Z. (2015). A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking. Leukemia, 29(4), 776–782.
Ratajczak, M. Z., Ratajczak, J., & Kucia, M. (2019). Very small embryonic-like Stem cells (VSELs). Circ Res, 124(2), 208–210.
Smadja, D. M., Melero-Martin, J. M., Eikenboom, J., Bowman, M., Sabatier, F., & Randi, A. M. (2019). Standardization of methods to quantify and culture endothelial colony-forming cells derived from peripheral blood: Position paper from the International Society on thrombosis and haemostasis SSC. Journal of Thrombosis and Haemostasis, 17(7), 1190–1194.
Blandinieres, A., Randi, A. M., Paschalaki, K. E., Guerin, C. L., Melero-Martin, J. M., & Smadja, D. M. (2023). Results of an international survey about methods used to isolate human endothelial colony-forming cells (ECFCs): Guidance from the Scientific and Standardization Committee on Vascular Biology of the International Society of Thrombosis and hemostasis. J Thromb Haemost. ;S1538-7836(23)00498-1.
Sherman, S. E., Kuljanin, M., Cooper, T. T., Lajoie, G. A., & Hess, D. A. (2020). Purification and functional characterization of CD34-Expressing cell subsets following Ex vivo expansion of umbilical cord blood-derived endothelial colony-forming cells. Stem Cells and Development, 29(14), 895–910.
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This work was funded with grants from the French national agency for research ANR SARCODO (Fondation de France) and Mécénat Covid AP-HP.
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CG and DMS designed the study. CLG, LS, and LG performed the experiments and analyzed data. LS, CLG, JLD, PG and DMS interpreted and discussed results and wrote the paper. GG and JLD included patients in SARCODO. Authors declare that the submitted work is original and has not been published before and that the work is not under consideration for publication elsewhere.
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The studies involving human participants were reviewed and approved by Comité de protection des personnes Sud Ouest et Outre Mer IV. The patients/participants provided their written informed consent to participate in this study. The study was performed in accordance with the Declaration of Helsinki and a written consent form was signed by all patients included or their trusted relatives at the time of enrollment (SARCODO study; A0104831A; NCT04624997).
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Soret, L., Guerin, C.L., Goudot, G. et al. The Onset of Intussusceptive Angiogenesis in COVID-19 Patients Might Come from the Mobilization of Stem Cell Sub-Populations Expressing the Hemangioblast Marker CD143. Stem Cell Rev and Rep (2024). https://doi.org/10.1007/s12015-024-10727-1
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DOI: https://doi.org/10.1007/s12015-024-10727-1