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刺猬通路介导新型两阶段肝切除术诱导的小鼠早期肝再生加速。

Hedgehog pathway mediates early acceleration of liver regeneration induced by a novel two-staged hepatectomy in mice.

机构信息

Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland.

Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland.

出版信息

J Hepatol. 2017 Mar;66(3):560-570. doi: 10.1016/j.jhep.2016.10.014. Epub 2016 Oct 19.

Abstract

BACKGROUND & AIMS: ALPPS, a novel two-staged approach for the surgical removal of large/multiple liver tumors, combines portal vein ligation (PVL) with parenchymal transection. This causes acceleration of compensatory liver growth, enabling faster and more extensive tumor removal. We sought to identify the plasma factors thought to mediate the regenerative acceleration following ALPPS.

METHODS

We compared a mouse model of ALPPS against PVL and additional control surgeries (n=6 per group). RNA deep sequencing was performed to identify candidate molecules unique to ALPPS liver (n=3 per group). Recombinant protein and a neutralizing antibody combined with appropriate surgeries were used to explore candidate functions in ALPPS (n=6 per group). Indian hedgehog (IHH/Ihh) levels were assessed in human ALPPS patient plasma (n=6).

RESULTS

ALPPS in mouse confirmed significant acceleration of liver regeneration relative to PVL (p<0.001). Ihh mRNA, coding for a secreted ligand inducing hedgehog signaling, was uniquely upregulated in ALPPS liver (p<0.001). Ihh plasma levels rose 4h after surgery (p<0.01), along with hedgehog pathway activation and subsequent cyclin D1 induction in the liver. When combined with PVL, Ihh alone was sufficient to induce ALPPS-like acceleration of liver growth. Conversely, blocking Ihh markedly inhibited the accelerating effects of ALPPS. In the small cohort of ALPPS patients, IHH tended to be elevated early after surgery.

CONCLUSIONS

Ihh and hedgehog pathway activation provide the first mechanistic insight into the acceleration of liver regeneration triggered by ALPPS surgery. The accelerating potency of recombinant Ihh, and its potential effect in human ALPPS may lead to a clinical role for this protein.

LAY SUMMARY

ALPPS, a novel two-staged hepatectomy, accelerates liver regeneration, thereby helping to treat patients with otherwise unresectable liver tumors. The molecular mechanisms behind this accelerated regeneration are unknown. Here, we elucidate that Indian hedgehog, a secreted ligand important for fetal development, is a crucial mediator of the regenerative acceleration triggered by ALPPS surgery.

摘要

背景与目的

联合肝脏离断和门静脉结扎的分阶段肝切除术(ALPPS)是一种治疗大/多发肝脏肿瘤的新两阶段手术方法,它结合了门静脉结扎(PVL)和肝实质离断。这会加速代偿性肝生长,从而实现更快、更广泛的肿瘤切除。我们试图确定认为介导 ALPPS 后再生加速的血浆因子。

方法

我们将 ALPPS 的小鼠模型与 PVL 和其他对照手术进行了比较(每组 6 只)。进行 RNA 深度测序以鉴定 ALPPS 肝脏特有的候选分子(每组 3 只)。使用重组蛋白和中和抗体结合适当的手术来探索 ALPPS 中的候选功能(每组 6 只)。评估了人类 ALPPS 患者血浆中的印度刺猬(IHH/Ihh)水平(n=6)。

结果

在小鼠中,ALPPS 相对于 PVL 确认了肝再生的显著加速(p<0.001)。编码诱导 Hedgehog 信号的分泌配体的 Ihh mRNA 在 ALPPS 肝脏中特异性上调(p<0.001)。手术后 4 小时,Ihh 血浆水平升高(p<0.01),同时肝脏中的 Hedgehog 途径激活和随后的细胞周期蛋白 D1 诱导。当与 PVL 联合使用时,单独的 Ihh 足以诱导类似于 ALPPS 的肝生长加速。相反,阻断 Ihh 则显著抑制了 ALPPS 的加速作用。在 ALPPS 患者的小队列中,术后早期 IHH 趋于升高。

结论

Ihh 和 Hedgehog 途径激活为 ALPPS 手术触发的肝再生加速提供了第一个机制见解。重组 Ihh 的加速效力及其在人类 ALPPS 中的潜在作用可能会使该蛋白具有临床作用。

概要

联合肝脏离断和门静脉结扎的分阶段肝切除术(ALPPS)是一种新型的两阶段肝切除术,可加速肝脏再生,从而有助于治疗其他情况下无法切除的肝脏肿瘤的患者。这种加速再生的分子机制尚不清楚。在这里,我们阐明了印度刺猬,一种对胎儿发育很重要的分泌配体,是 ALPPS 手术触发的再生加速的关键介质。

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