肝血管内皮生长因子调节大鼠肝窦内皮细胞祖细胞的募集。
Hepatic vascular endothelial growth factor regulates recruitment of rat liver sinusoidal endothelial cell progenitor cells.
机构信息
Division of Gastrointestinal and Liver Disease and the University of Southern California Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
出版信息
Gastroenterology. 2012 Dec;143(6):1555-1563.e2. doi: 10.1053/j.gastro.2012.08.008. Epub 2012 Aug 15.
BACKGROUND & AIMS: After liver injury, bone marrow-derived liver sinusoidal endothelial cell progenitor cells (BM SPCs) repopulate the sinusoid as liver sinusoidal endothelial cells (LSECs). After partial hepatectomy, BM SPCs provide hepatocyte growth factor, promote hepatocyte proliferation, and are necessary for normal liver regeneration. We examined how hepatic vascular endothelial growth factor (VEGF) regulates recruitment of BM SPCs and their effects on liver injury.
METHODS
Rats were given injections of dimethylnitrosamine to induce liver injury, which was assessed by histology and transaminase assays. Recruitment of SPCs was analyzed by examining BM SPC proliferation, mobilization to the circulation, engraftment in liver, and development of fenestration (differentiation).
RESULTS
Dimethylnitrosamine caused extensive denudation of LSECs at 24 hours, followed by centrilobular hemorrhagic necrosis at 48 hours. Proliferation of BM SPCs, the number of SPCs in the bone marrow, and mobilization of BM SPCs to the circulation increased 2- to 4-fold by 24 hours after injection of dimethylnitrosamine; within 5 days, 40% of all LSECs came from engrafted BM SPCs. Allogeneic resident SPCs, infused 24 hours after injection of dimethylnitrosamine, repopulated the sinusoid as LSECs and reduced liver injury. Expression of hepatic VEGF messenger RNA and protein increased 5-fold by 24 hours after dimethylnitrosamine injection. Knockdown of hepatic VEGF with antisense oligonucleotides completely prevented dimethylnitrosamine-induced proliferation of BM SPCs and their mobilization to the circulation, reduced their engraftment by 46%, completely prevented formation of fenestration after engraftment as LSECs, and exacerbated dimethylnitrosamine injury.
CONCLUSIONS
BM SPC recruitment is a repair response to dimethylnitrosamine liver injury in rats. Hepatic VEGF regulates recruitment of BM SPCs to liver and reduces this form of liver injury.
背景与目的
肝损伤后，骨髓来源的肝窦内皮细胞前体细胞（BM SPCs）会在窦状内皮细胞（LSECs）中重新填充。在部分肝切除术后，BM SPCs 提供肝细胞生长因子，促进肝细胞增殖，是正常肝再生所必需的。我们研究了肝血管内皮生长因子（VEGF）如何调节 BM SPC 的募集及其对肝损伤的影响。
方法
大鼠给予二甲基亚硝胺注射诱导肝损伤，通过组织学和转氨酶检测评估。通过检测 BM SPC 增殖、动员到循环、在肝内植入和形成窗孔（分化）来分析 SPC 的募集。
结果
二甲基亚硝胺在 24 小时内导致 LSEC 广泛剥脱，48 小时后出现中央小叶出血性坏死。BM SPC 增殖、骨髓中 SPC 数量和 BM SPC 动员到循环中的数量在二甲基亚硝胺注射后 24 小时增加 2-4 倍；在 5 天内，所有 LSEC 的 40%来自植入的 BM SPC。二甲基亚硝胺注射后 24 小时输注同种异体常驻 SPC，可作为 LSEC 重新填充窦状内皮，并减少肝损伤。注射二甲基亚硝胺后 24 小时，肝 VEGF 信使 RNA 和蛋白的表达增加 5 倍。用反义寡核苷酸敲低肝 VEGF 完全阻止了 BM SPC 的增殖和动员到循环中，使它们的植入减少了 46%，完全阻止了植入后作为 LSEC 的窗孔形成，并加剧了二甲基亚硝胺的损伤。
结论
BM SPC 的募集是大鼠二甲基亚硝胺肝损伤的修复反应。肝 VEGF 调节 BM SPC 向肝的募集，并减少这种形式的肝损伤。
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