Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China.
Department of Biological Treatment Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China.
World J Gastroenterol. 2018 Mar 14;24(10):1107-1119. doi: 10.3748/wjg.v24.i10.1107.
To establish a rat model for evaluating the maturity of liver regeneration derived from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).
In the present study, ALPPS, partial hepatecotmy (PHx), and sham rat models were established initially, which were validated by significant increase of proliferative markers including Ki-67, proliferating cell nuclear antigen, and cyclin D1. In the setting of accelerated proliferation in volume at the second and fifth day after ALPPS, the characteristics of newborn hepatocytes, as well as specific markers of progenitor hepatic cell, were identified. Afterwards, the detection of liver function followed by cluster analysis of functional gene expression were performed to evaluate the maturity.
Compared with PHx and sham groups, the proliferation of FLR was significantly higher in ALPPS group ( = 0.023 and 0.001 at second day, = 0.034 and < 0.001 at fifth day after stage I). Meanwhile, the increased expression of proliferative markers including Ki-67, proliferating cell nuclear antigen, and cyclin D1 verified the accelerated liver regeneration derived from ALPPS procedure. However, ALPPS-induced Sox9 positive hepatocytes significantly increased beyond the portal triad, which indicated the progenitor hepatic cell was potentially involved. And the characteristics of ALPPS-induced hepatocytes indicated the lower expression of hepatocyte nuclear factor 4 and anti-tryptase in early proliferative stage. Both suggested the immaturity of ALPPS-derived liver regeneration. Additionally, the detection of liver function and functional genes expression confirmed the immaturity of renascent hepatocytes derived in early stage of ALPPS-derived liver regeneration.
Our study revealed the immaturity of ALPPS-derived proliferation in early regenerative response, which indicated that the volumetric assessment overestimated the functional proliferation. This could be convincing evidence that the stage II of ALPPS should be performed prudently in patients with marginally adequate FLR, as the ALPPS-derived proliferation in volume lags behind the functional regeneration.
建立评估联合肝脏分隔和门静脉结扎的分期肝切除术（ALPPS）衍生肝再生成熟度的大鼠模型。
本研究首先建立了 ALPPS、部分肝切除术（PHx）和假手术大鼠模型，通过增殖标志物 Ki-67、增殖细胞核抗原和细胞周期蛋白 D1 的显著增加来验证。在 ALPPS 后第 2 天和第 5 天体积快速增殖的情况下，鉴定了新生肝细胞的特征以及祖细胞肝的特定标志物。然后，进行肝功能检测，对功能基因表达进行聚类分析，以评估成熟度。
与 PHx 和假手术组相比，ALPPS 组 FLR 的增殖明显更高（第 2 天 = 0.023 和 0.001，第 5 天 = 0.034 和 <0.001）。同时，Ki-67、增殖细胞核抗原和细胞周期蛋白 D1 等增殖标志物的表达增加证实了源自 ALPPS 手术的加速肝再生。然而，ALPPS 诱导的 Sox9 阳性肝细胞明显超出门三联体增加，这表明祖细胞肝可能参与其中。并且 ALPPS 诱导的肝细胞的特征表明，在早期增殖阶段，肝细胞核因子 4 和抗胰蛋白酶的表达较低。这两者均表明 ALPPS 衍生的肝再生不成熟。此外，肝功能检测和功能基因表达证实了早期 ALPPS 衍生肝再生中新生肝细胞的不成熟。
我们的研究揭示了早期再生反应中 ALPPS 衍生增殖的不成熟，这表明体积评估高估了功能增殖。这可以作为令人信服的证据，即对于边缘性足够的 FLR 患者，应谨慎进行 ALPPS 的 II 期手术，因为在体积上，ALPPS 衍生的增殖落后于功能再生。
