Gomez-Salinero Jesus M, Itkin Tomer, Houghton Sean, Badwe Chaitanya, Lin Yang, Kalna Viktoria, Dufton Neil, Peghaire Claire R, Yokoyama Masataka, Wingo Matthew, Lu Tyler M, Li Ge, Xiang Jenny Zhaoying, Hsu Yen-Michael Sheng, Redmond David, Schreiner Ryan, Birdsey Graeme M, Randi Anna M, Rafii Shahin
Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
National Heart and Lung Institute, Imperial College London, London, UK.
Nat Cardiovasc Res. 2022 Oct;1:882-899. doi: 10.1038/s44161-022-00128-3. Epub 2022 Oct 6.
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.
当前的理论认为，在成年期，内皮细胞（ECs）处于一种不可改变的稳定稳态。相比之下，我们在此表明，内皮细胞命运和功能的维持是相互关联的主动过程，这仅依赖于两种ETS转录因子（TFs）ERG和Fli1的组成性协同作用。虽然单独缺失Fli1或ERG会表现出轻微的血管功能障碍，但在成年内皮细胞中联合基因缺失会导致急性血管病变和多器官衰竭，这是由于内皮细胞命运和完整性丧失、过度炎症反应和自发性血栓形成，最终导致死亡。ERG和Fli1共同缺失会导致泛血管和器官特异性血管核心基因的快速转录沉默，同时炎症和凝血途径失调。血管过度炎症反应会导致造血功能受损并伴有髓系偏移。因此，在成人间充质基质细胞中强制表达ERG和FLI1可激活血管程序和功能，从而使可灌注血管网络得以植入。全基因组关联研究（GWAS）分析表明，血管疾病与FLI1/Erg突变有关。ERG和Fli1的组成性表达维持了成年血管中内皮细胞的命运、生理功能和恢复能力；而它们的功能丧失可能会导致全身性人类疾病。
