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Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration

机译：肝再生需要来自窦状内皮的诱导性血管分泌信号

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摘要

During embryogenesis, endothelial cells induce organogenesis before the development of circulation. 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 haematopoiesis. However, the precise mechanism by which tissue-specific subsets of endothelial cells promote prganogenesis 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 hepato-vascular mass (days 4-8 after partial hepatectomy) by inhibiting upregulation of the endothelial-cell-specific transcription factor Idl. Accordingly, Idl -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-Idl-dependent pro-liferative 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.
机译：在胚胎发生期间，内皮细胞在循环发展之前诱导器官发生。这些发现表明，内皮细胞不仅形成输送营养和氧气的被动导管，而且建立了指导性的血管生境，通过精心设计旁分泌的营养素刺激器官再生，其方式类似于支持造血功能的内皮细胞衍生的血管分泌因子。但是，尚不知道内皮细胞的组织特异性亚群促进成年发生的确切机制。在这里，我们证明了肝窦内皮细胞（LSEC）构成了独特的表型和功能定义的VEGFR3〜+ CD34〜-VEGFR2〜+ VE-cadherin〜+ FactorVIII〜+ CD45〜-内皮细胞群，这些内皮细胞通过释放血管分泌的营养因子启动并维持由70％的部分肝切除术引起的肝再生。肝部分切除后，残留的肝血管仍完整无缺氧或结构性损伤，从而可以进行生理性肝再生研究。使用此模型，我们显示LSEC中的血管内皮生长因子（VEGF）-A受体2（VEGFR2）的诱导性遗传消融损害了肝细胞增殖的初始爆发（部分肝切除术后1-3天）和随后的肝细胞重构。通过抑制内皮细胞特异性转录因子Idl的上调来调节肝血管肿块（部分肝切除术后4-8天）。因此，由于LSEC衍生的血管分泌因子，包括肝细胞生长因子（HGF）和Wnt2的表达减少，Idl缺陷型小鼠还在整个肝脏再生中表现出缺陷。值得注意的是，在体外共培养中，LSEC中的VEGFR2-Id1激活可刺激肝细胞增殖。确实，脾脏内移植Wnt2和HGF（Id1〜（-/-）Wnt2〜+ HGF〜+ LSECs）转导的Id1〜（+ / +）或Id1〜（-/-）LSECs在小鼠中重建了诱导性血管生态位。 Id1〜（-/-）小鼠的肝正弦曲线，启动并恢复肝血管再生。因此，在生理性肝再生的早期阶段，VEGFR2-Id1介导的LSECs通过释放血管分泌因子Wnt2和HGF诱导肝血管新生，从而引起肝细胞增殖。随后，VEGFR2-Id1依赖性增殖血管新生重建肝脏肿块。诱导性VEGFR2〜+ Id1〜+ Wnt2〜+ HGF〜+ LSEC与肝细胞的治疗性联合移植提供了实现持久肝再生的有效策略。

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  • 来源
    《Nature》 |2010年第7321期|p.310-315121|共7页
  • 作者

    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;

  • 作者单位

    Howard Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA;

    rnHoward Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA;

    rnHoward Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA;

    rnHoward Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA;

    rnHoward Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA;

    rnRonald O. Perelman and Claudia Cohen Center for Reproductive Medicine, New York, New York 10065, USA;

    rnDepartment of Surgery, Weill Cornell Medical College, New York, New York 10065, USA;

    rnHoward Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA;

    rnHoward Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA;

    rnDepartment of Pediatrics, Weill Cornell Medical College, New York, New York, 10065, USA;

    rnGraduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara, Japan;

    rnHoward Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA Bioengineering Program, Hofstra University, Hempstead, New York 11549, USA;

    rnHoward Hughes Medical Institute, Ansary Stem Cell Institute, and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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