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Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia.

ABSTRACT: BACKGROUND:The role of vascular endothelium in acute promyelocytic leukaemia (APL) remains unknown. We aimed to investigate the mechanisms by which APL cells interact with endothelial cells (ECs) and to further explore how the endothelium affects bleeding as well as therapeutic interventions. METHOD:APL cells and an original APL cell line, NB4 cells, were used for experiments. The effects of leukaemic cells on ECs were analyzed in vitro and in vivo. Moreover, the endothelial barrier function and procoagulant activity were detected. An APL mouse model was established for in vivo studies. FINDINGS:APL cells interacted with ECs via ICAM-1 and VCAM-1 receptors to disrupt endothelial integrity. This binding activated MLCK signaling, resulting in the trans-endothelial passage of protein and red blood cells (RBCs). Combined treatment with asiatic acid or anti-adhesion receptor antibody inhibited the response of ECs to APL cells, thereby preventing APL-associated haemorrhage in vitro and in vivo. Activated ECs exhibited a procoagulant phenotype after phosphatidylserine exposure. Plasma from APL patients formed a thin fibrin network between procoagulant ECs, and this intercellular fibrin decreased the passage of albumin and RBCs. Ex vivo addition of fibrinogen further enhanced this barrier function in a dose-dependent manner. INTERPRETATION:Endothelial damage induced by leukaemic cell adherence promotes haemorrhaging in APL. Stabilization of ECs, decreasing adhesion receptor expression, and increasing fibrinogen transfusion levels may be a new therapeutic avenue to alleviate this fatal bleeding complication. FUNDING:National Science Foundation of China (81670128, 81873433).

SUBMITTER: Wang C

PROVIDER: S-EPMC7501057 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia.

Wang Chunxu C Yu Muxin M Zhou Peng P Li Baorong B Liu Yingmiao Y Wang Lixiu L Chen Xiaojing X Du Jingwen J Wang Yufeng Y Zhang Jinming J Jing Haijiao H Feng Yiming Y Zhang Yue Y Li Yueyue Y Dong Zengxiang Z Fang Shaohong S Novakovic Valerie A VA Zhou Jin J Shi Jialan J

EBioMedicine 20200916

<h4>Background</h4>The role of vascular endothelium in acute promyelocytic leukaemia (APL) remains unknown. We aimed to investigate the mechanisms by which APL cells interact with endothelial cells (ECs) and to further explore how the endothelium affects bleeding as well as therapeutic interventions.<h4>Method</h4>APL cells and an original APL cell line, NB4 cells, were used for experiments. The effects of leukaemic cells on ECs were analyzed in vitro and in vivo. Moreover, the endothelial barri ...[more]

PMID: 32949998

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Project description:A modular tissue engineering approach may have advantages over current therapies in providing rapid and sustained revascularization of ischemic tissue. In this study, modular protein microbeads were prepared from pure fibrin (FIB) and collagen-fibrin composites (COL-FIB) using a simple water-in-oil emulsification technique. Human endothelial cells and fibroblasts were embedded directly in the microbead matrix. The resulting microbeads were generally spheroidal with a diameter of 100-200?m. Cell viability was high (75-80% viable) in microbeads, but was marginally lower than in bulk hydrogels of corresponding composition (85-90% viable). Cell proliferation was significantly greater in COL-FIB microbeads after two weeks in culture, compared to pure FIB microbeads. Upon embedding of microbeads in a surrounding fibrin hydrogel, endothelial cell networks formed inside the microbead matrix and extended into the surrounding matrix. The number of vessel segments, average segment length, and number of branch points was higher in FIB samples, compared to COL-FIB samples, resulting in significantly longer total vessel networks. Anastomosis of vessel networks from adjacent microbeads was also observed. These studies demonstrate that primitive vessel networks can be formed by modular protein microbeads containing embedded endothelial cells and fibroblasts. Such microbeads may find utility as prevascularized tissue modules that can be delivered minimally invasively as a therapy to restore blood flow to ischemic tissues.Vascularization is critically important for tissue engineering and regenerative medicine, and materials that support and/or promote neovascularization are of value both for translational applications and for mechanistic studies and discovery-based research. Therefore, we fabricated small modular microbeads formulated from pure fibrin (FIB) and collagen-fibrin (COL-FIB) containing endothelial cells and supportive fibroblasts. We explored how cells encapsulated within these materials form microvessel-like networks both within and outside of the microbeads when embedded in larger 3D matrices. FIB microbeads were found to initiate more extensive sprouting into the surrounding ECM in vitro. These results represent an important step towards our goal of developing injectable biomaterial modules containing preformed vascular units that can rapidly restore vascularization to an ischemic tissue in vivo.

Dataset Information

Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia.

Publications

Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia.

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