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Nature:肝脏再生的信号

来源:Nature 2010-11-15 13:57

越来越多的证据表明,内皮细胞并不简单是提供氧气和营养物的被动通道。例如,在胚胎生成过程中,它们在循环系统形成之前诱导器官生成。

现在,用一个70%肝切除的肝脏再生小鼠模型所进行的实验,显示了内皮细胞在切除手术后维持肝脏再生的一个分子通道。在所定义的肝脏内皮细胞的一个亚组中VEGFR2的激发,导致内皮特定转录因子Id1的上调,这种上调反过来又诱导Wnt2和肝细胞生长因子(HGF)的分泌,它又触发肝细胞的增殖。

这表明,来自促进肝再生的脉管系统的诱导性信号,有可能被用来在这些手术之后启动和加速肝脏恢复。(生物谷Bioon.com)

生物谷推荐英文摘要:

Nature doi:10.1038/nature09493

Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration
Bi-Sen Ding,Daniel J. Nolan,Jason M. Butler,Daylon James,Alexander O. Babazadeh,Zev Rosenwaks,Vivek Mittal,Hideki Kobayashi,Koji Shido,David Lyden,Thomas N. Sato,Sina Y. Rabbany& Shahin Rafii

During embryogenesis, endothelial cells induce organogenesis before the development of circulation1, 2, 3, 4. These findings suggest that endothelial cells not only form passive conduits to deliver nutrients and oxygen, but also establish an instructive vascular niche, which through elaboration of paracrine trophogens stimulates organ regeneration, in a manner similar to endothelial-cell-derived angiocrine factors that support haematopoiesis5, 6, 7. However, the precise mechanism by which tissue-specific subsets of endothelial cells promote organogenesis in adults is unknown. Here we demonstrate that liver sinusoidal endothelial cells (LSECs) constitute a unique population of phenotypically and functionally defined VEGFR3+CD34?VEGFR2+VE-cadherin+FactorVIII+CD45? endothelial cells, which through the release of angiocrine trophogens initiate and sustain liver regeneration induced by 70% partial hepatectomy. After partial hepatectomy, residual liver vasculature remains intact without experiencing hypoxia or structural damage, which allows study of physiological liver regeneration. Using this model, we show that inducible genetic ablation of vascular endothelial growth factor (VEGF)-A receptor-2 (VEGFR2) in the LSECs impairs the initial burst of hepatocyte proliferation (days 1–3 after partial hepatectomy) and subsequent reconstitution of the hepatovascular mass (days 4–8 after partial hepatectomy) by inhibiting upregulation of the endothelial-cell-specific transcription factor Id1. Accordingly, Id1-deficient mice also manifest defects throughout liver regeneration, owing to diminished expression of LSEC-derived angiocrine factors, including hepatocyte growth factor (HGF) and Wnt2. Notably, in in vitro co-cultures, VEGFR2-Id1 activation in LSECs stimulates hepatocyte proliferation. Indeed, intrasplenic transplantation of Id1+/+ or Id1?/? LSECs transduced with Wnt2 and HGF (Id1?/?Wnt2+HGF+ LSECs) re-establishes an inductive vascular niche in the liver sinusoids of the Id1?/? mice, initiating and restoring hepatovascular regeneration. Therefore, in the early phases of physiological liver regeneration, VEGFR2-Id1-mediated inductive angiogenesis in LSECs through release of angiocrine factors Wnt2 and HGF provokes hepatic proliferation. Subsequently, VEGFR2-Id1-dependent proliferative angiogenesis reconstitutes liver mass. Therapeutic co-transplantation of inductive VEGFR2+Id1+Wnt2+HGF+ LSECs with hepatocytes provides an effective strategy to achieve durable liver regeneration.

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