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BMP-9 interferes with liver regeneration and promotes liver fibrosis
来源: | 作者:pmo597dc1 | 时间 :2017-11-06 | 611 次浏览 | 分享到:

Hepatology November 4, 2017

ABSTRACT

Objective Bone morphogenetic protein (BMP)-9, a member of the transforming growth factor-β family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues including bone and endothelium, but little is known about its hepatic

functions in health and disease. Design Levels of BMP-9 and its receptors were analyzed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice. Results Quiescent and activated HSCs were identified as major BMP-9 producing liver cell type. BMP-9 stimulation of cultured hepatocytes inhibited proliferation, epithelial to mesenchymal transition and preserved expression of important metabolic enzymes such as cytochrome P450. Acute liver injury caused by partial hepatectomy or single injections of carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) into mice resulted in transient downregulation of hepatic BMP-9 mRNA expression. Correspondingly, LPS stimulation led to downregulation of BMP-9 expression in cultured HSCs. Application of BMP-9 after partial hepatectomy significantly enhanced liver damage and disturbed the proliferative response. Chronic liver damage in BMP-9- deficient mice or in mice adenovirally overexpressing the selective BMP-9 antagonist activin receptor-like kinase 1-Fc resulted in reduced deposition of collagen and subsequent fibrosis. Conclusions Constitutive expression of low levels of BMP-9 stabilises hepatocyte function in the healthy liver. Upon HSC activation, endogenous BMP-9 levels increase in vitro and in vivo and high levels of BMP-9 cause enhanced damage upon acute or chronic injury.

 

中文解读

BMP-9是由肝脏产生并且不断分泌入血液的转化生长因子-β家族细胞因子中的一员。以往的研究报道BMP-9具有抗增殖和稳定成熟健康血管的作用。BMP-9诱导肝癌细胞从上皮向间充质态转化,并且其蛋白水平与患者样本中的肝癌侵袭程度相关。本实验首次发现静息态及活化的肝星状细胞是产生BMP-9的主要细胞。肝纤维化激活状态下,HSC表达和分泌BMP-9水平增加。基因敲除及抑制BMP-9的小鼠在多次CCl4注射引发的慢性肝损伤中,纤维化程度显着减轻。低水平的BMP-9能够促进急性肝损伤模型小鼠的肝脏愈合及再生。此外,研究发现BMP-9具有抑制增殖及维持健康肝细胞稳态的作用,包括维持细胞极性和代谢酶如P450的表达。此研究结果对临床急慢性肝损伤的治疗恢复和肝再生具有借鉴意义。