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• W4387376593 abstract "In this issue of Cell Stem Cell, Kawakami et al. develop a SARS-CoV-2 infection-competent, progenitor-derived, human vascular organoid model and uncover a role for complement factor D (CFD) in mediating microvascular immunothrombosis. This model may be applied to conditions where microvascular disease plays a major pathogenic role. In this issue of Cell Stem Cell, Kawakami et al. develop a SARS-CoV-2 infection-competent, progenitor-derived, human vascular organoid model and uncover a role for complement factor D (CFD) in mediating microvascular immunothrombosis. This model may be applied to conditions where microvascular disease plays a major pathogenic role. COVID-19, caused by the SARS-CoV-2 virus, has led to an unprecedented global health crisis uniting the medical and scientific communities. Substantial research progress has highlighted the complex pathogenic interplay between viral infections, the immune system, and the vasculature.1Gu S.X. Tyagi T. Jain K. Gu V.W. Lee S.H. Hwa J.M. Kwan J.M. Krause D.S. Lee A.I. Halene S. et al.Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.Nat. Rev. Cardiol. 2021; 18: 194-209https://doi.org/10.1038/s41569-020-00469-1Crossref PubMed Scopus (237) Google Scholar,2Goshua G. Pine A.B. Meizlish M.L. Chang C.H. Zhang H. Bahel P. Baluha A. Bar N. Bona R.D. Burns A.J. et al.Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study.Lancet. Haematol. 2020; 7: e575-e582https://doi.org/10.1016/S2352-3026(20)30216-7Abstract Full Text Full Text PDF PubMed Scopus (704) Google Scholar One emerging manifestation of COVID-19 is microvascular immunothrombosis, where an intense immune response elicits a complex combination of coagulopathy, thrombocytopathy, and endotheliopathy, ultimately leading to the formation of thrombi within the microvasculature. Excessive microvascular thrombi can result in multi-organ failure, contributing significantly to morbidity and mortality.3McFadyen J.D. Stevens H. Peter K. The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications.Circ. Res. 2020; 127: 571-587https://doi.org/10.1161/CIRCRESAHA.120.317447Crossref PubMed Scopus (374) Google Scholar Surprisingly, the precise molecular mechanisms of microvascular immunothrombosis in COVID-19 remain challenging given the limitations of the animal models in accurate representation of the complex human microvascular environment with SARS-CoV-2 infection. Human organoids represent a remarkable advancement in regenerative medicine that can mimic the architecture and complex physiology of many different organs. The self-assembly of iPSC-derived endothelial cells and mesenchymal stem cells into functional microvascular networks can produce novel vascular organoids that can recapitulate the physiology and environment of human blood vessels.4Orlova V.V. van den Hil F.E. Petrus-Reurer S. Drabsch Y. Ten Dijke P. Mummery C.L. Generation, expansion and functional analysis of endothelial cells and pericytes derived from human pluripotent stem cells.Nat. Protoc. 2014; 9: 1514-1531https://doi.org/10.1038/nprot.2014.102Crossref PubMed Scopus (241) Google Scholar,5Wimmer R.A. Leopoldi A. Aichinger M. Wick N. Hantusch B. Novatchkova M. Taubenschmid J. Hämmerle M. Esk C. Bagley J.A. et al.Human blood vessel organoids as a model of diabetic vasculopathy.Nature. 2019; 565: 505-510https://doi.org/10.1038/s41586-018-0858-8Crossref PubMed Scopus (376) Google Scholar,6Monteil V. Kwon H. Prado P. Hagelkrüys A. Wimmer R.A. Stahl M. Leopoldi A. Garreta E. Hurtado Del Pozo C. Prosper F. et al.Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2.Cell. 2020; 181: 905-913.e7https://doi.org/10.1016/j.cell.2020.04.004Abstract Full Text Full Text PDF PubMed Scopus (1507) Google Scholar In this issue of Cell Stem Cell, the study by Kawakami et al. expands upon these tools by developing a SARS-CoV-2-competent vascular organoid derived from human iPSCs. Infection with SARS-CoV-2 stimulated the immune and vascular responses observed in severe COVID-19 patients, including cytokine upregulation, increased markers of endotheliopathy, and transcriptomic signatures of complement activation. Moreover, anastomosing the vascular organoid into a murine host cerebral circulatory system not only recapitulated the thrombotic complications observed in COVID-19 patients but also offered insights into the mechanisms driving complement-mediated thrombosis in the microvasculature. The complement system, while normally beneficial in the initial immune response to infections, can become pathogenic during states of uncontrolled activation. Excessive complement activation has been recognized as a pathologic feature of severe SARS-CoV-2 infection, and previous studies have shown that the alternative pathway is activated in COVID-19 patients and is associated with endothelial injury and hypercoagulability.7Ma L. Sahu S.K. Cano M. Kuppuswamy V. Bajwa J. McPhatter J. Pine A. Meizlish M.L. Goshua G. Chang C.H. et al.Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection.Sci. Immunol. 2021; 6eabh2259https://doi.org/10.1126/sciimmunol.abh2259Crossref Scopus (59) Google Scholar Kawakami et al. reinforced and expanded upon these findings through longitudinal serum proteomic profiling of critically ill COVID-19 patients showing aberrant signatures of complement activation and increased markers of endotheliopathy and hypercoagulability. Utilizing vascular organoids and infection with SARS-CoV-2 in vitro, the authors also observed transcriptomic signatures of complement activation. By transplanting the human vascular organoid under mouse cranial window, the authors substantiated their findings by showing that the extracellular domain (ECD) of SARS-CoV-2 spike protein is sufficient to trigger alternative complement activation, formation of neutrophil extracellular traps (NETs), and human blood vessel occlusion (Figure 1). Furthermore, a complement factor B small-molecule inhibitor of the alternative pathway prevented thrombus formation in the transplanted human vascular organoid model. Finally, by using a non-human primate model of SARS-CoV-2 infection8Aid M. Busman-Sahay K. Vidal S.J. Maliga Z. Bondoc S. Starke C. Terry M. Jacobson C.A. Wrijil L. Ducat S. et al.Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques.Cell. 2020; 183: 1354-1366.e13https://doi.org/10.1016/j.cell.2020.10.005Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar and building on the prior report that complement factor D (CFD) is essential for alternative complement pathway by SARS-CoV-2,9Yu J. Yuan X. Chen H. Chaturvedi S. Braunstein E.M. Brodsky R.A. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition.Blood. 2020; 136: 2080-2089https://doi.org/10.1182/blood.2020008248Crossref PubMed Google Scholar Kawakami et al. demonstrated that a long-acting monoclonal antibody to complement factor D of the alternative pathway reduces inflammation and thrombosis in non-human primates in vivo. The implications of the study by Kawakami et al. extend well beyond COVID-19 and may provide unique insights into the molecular and cellular mechanisms of microvascular thrombosis including thrombotic microangiopathies, sepsis, vasculitis, autoimmune disease, and sickle cell disease. The organoid can be used to mimic different vascular beds and be transplanted into different organs. Such a system would permit evaluation of therapeutics and the addition of risk factors (e.g., diabetes mellitus, obesity, aging, etc.) associated with high COVID-19 mortality to settle key controversial and unanswered questions, where stressors may uncover underlying pathophysiologic mechanisms of disease progression.10Reiterer M. Rajan M. Gómez-Banoy N. Lau J.D. Gomez-Escobar L.G. Ma L. Gilani A. Alvarez-Mulett S. Sholle E.T. Chandar V. et al.Hyperglycemia in acute COVID-19 is characterized by insulin resistance and adipose tissue infectivity by SARS-CoV-2.Cell Metab. 2021; 33: 2174-2188.e5https://doi.org/10.1016/j.cmet.2021.09.009Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Human cell organoids open new opportunities for both modeling diseases where animal models are inadequate and preclinical testing of therapeutics that target molecular processes exclusive to human subjects. Furthermore, application of human iPSC-derived organoids allows analyses of genetic factors involved in disease pathogenesis and thus the development of personalized medicines. However, as with any innovative technique, challenges remain to refine and optimize the model. Determining the detailed structural and functional omics characteristics of the vascular organoid cells, and comparing them to that of normal human vascular physiology, will be important. Overall, the insights gained from this study by Kawakami et al. substantially improve our understanding of the mechanism of microvascular immunothrombotic events in COVID-19 patients and provide the basis for targeted therapeutics. The authors declare no competing interests." @default.
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• W4387376593 title "Fishing for “complements” with vascular organoid models of microvascular disease" @default.
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