Cooperative ETS Transcription Factors Enforce Adult Endothelial Cell Fate and Cardiovascular Homeostasis.

Autor: Gomez-Salinero JM; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Itkin T; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Houghton S; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Badwe C; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Lin Y; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Kalna V; National Heart and Lung Institute, Imperial College London, London, UK.; Human Genetics and Computational Biology GSK, UK (current address)., Dufton N; National Heart and Lung Institute, Imperial College London, London, UK.; Queen Mary University of London, Centre for Microvascular Research, William Harvey Research Centre, UK (current address)., Peghaire CR; National Heart and Lung Institute, Imperial College London, London, UK.; University of Bordeaux, Inserm UMR1034, Biology of Cardiovascular Diseases, Pessac, France (current address)., Yokoyama M; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Wingo M; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Lu TM; Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Li G; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Xiang JZ; Genomics Resources Core Facility, Weill Cornell Medicine, NY, USA., Hsu YS; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA.; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA (current address).; Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA (current address)., Redmond D; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Schreiner R; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA., Birdsey GM; National Heart and Lung Institute, Imperial College London, London, UK., Randi AM; National Heart and Lung Institute, Imperial College London, London, UK., Rafii S; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, NY, USA.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2022 Oct; Vol. 1, pp. 882-899. Date of Electronic Publication: 2022 Oct 06.
DOI: 10.1038/s44161-022-00128-3
Abstrakt: Current dogma dictates that during adulthood, endothelial cells (ECs) are locked in an immutable stable homeostatic state. By contrast, herein we show that maintenance of EC fate and function are linked and active processes, which depend on the constitutive cooperativity of only two ETS-transcription factors (TFs) ERG and Fli1. While deletion of either Fli1 or ERG manifest subtle vascular dysfunction, their combined genetic deletion in adult EC results in acute vasculopathy and multiorgan failure, due to loss of EC fate and integrity, hyperinflammation, and spontaneous thrombosis, leading to death. ERG and Fli1 co-deficiency cause rapid transcriptional silencing of pan- and organotypic vascular core genes, with dysregulation of inflammation and coagulation pathways. Vascular hyperinflammation leads to impaired hematopoiesis with myeloid skewing. Accordingly, enforced ERG and FLI1 expression in adult human mesenchymal stromal cells activates vascular programs and functionality enabling engraftment of perfusable vascular network. GWAS-analysis identified vascular diseases are associated with FLI1/Erg mutations. Constitutive expression of ERG and Fli1 uphold EC fate, physiological function, and resilience in adult vasculature; while their functional loss can contribute to systemic human diseases.
Competing Interests: Competing Interest Statement: Shahin Rafii is the co-founder and non-paid consultant to Angiocrine Bioscience, CA.
Databáze: MEDLINE
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