Study on relationship between remnant liver regeneration after ALPPS and Lgr5 protein expression in rat_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Weiwei , FANG Zheng , XIA Xianjun , BAI Yang , XIE Weixuan , PU Yifeng ,  LUO Kunlun

Department of Hepatobiliary Surgery, The 904th Hospital of Joint Logistic Support Force of PLA, Wuxi, Jiangsu 214044, P. R. China;

Corresponding author：

LUO Kunlun, Email: lkl197041@163.com

Keywords：

Lgr5; associating liver partition and portal vein ligation for staged hepatectomy; liver regeneration; rat

DOI：

10.7507/1007-9424.202102032

Video：

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Objective To investigate the expression of Lgr5 protein in regeneration tissue of remnant liver after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and its significance.Methods A total of 120 male SD rats (200–240 g) were randomly equally divided into sham operation (SO) group, portal vein ligation (PVL) group, and ALPPS group using random number table method. The liver regeneration rate (LRR), liver function (AST and ALT), and the expressions of Ki-67 and Lgr5 in the right middle lobe of the liver were observed at day 1, 2, 4, and 7 after surgery.Results Compared with SO group, the LRRs and the Ki-67 protein expression positive rates and Lgr5 related protein expression levels in the right middle lobe of liver tissue were increased in the PVL group and ALPPS group at day 1, 2, and 4 after surgery (P<0.05), and the LRR was still increased at day 7 after surgery (P<0.05). The LRRs at day 4 and 7 after surgery in the ALPPS group were higher than those in the PVL group (P<0.05), the Ki-67 protein expression positive rates and Lgr5 related protein expression levels at day 2 and 4 after surgery in the ALPPS group were higher than those in the PVL group (P<0.05). The AST and ALT levels at day 1 and 2 after surgery in the ALPPS group and PVL group were higher than those in the SO group (P<0.05), which at day 1 after surgery in the ALPPS group were higher than those in the PVL group (P<0.05), but which returned to normal on day 4 after surgery.Conclusions ALPPS could promote liver regeneration better. Lgr5 is closely related to liver regeneration after ALPPS. Liver stem cells might be involved in liver regeneration after ALPPS.

Citation： LIU Weiwei, FANG Zheng, XIA Xianjun, BAI Yang, XIE Weixuan, PU Yifeng, LUO Kunlun. Study on relationship between remnant liver regeneration after ALPPS and Lgr5 protein expression in rat. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(10): 1275-1279. doi: 10.7507/1007-9424.202102032 Copy

1.	Fonseca AL, Cha CH. Hepatocellular carcinoma: a comprehensive overview of surgical therapy. J Surg Oncol, 2014, 110(6): 712-719.
2.	Clark ME, Smith RR. Liver-directed therapies in metastatic colorectal cancer. J Gastrointest Oncol, 2014, 5(5): 374-387.
3.	Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: A preliminary report. Surgery, 1990, 107(5): 521-527.
4.	van den Esschert JW, van Lienden KP, Alles LK, et al. Liver regeneration after portal vein embolization using absorbable and permanent embolization materials in a rabbit model. Ann Surg, 2012, 255(2): 311-318.
5.	Wilms C, Mueller L, Lenk C, et al. Comparative study of portal vein embolization versus portal vein ligation for induction of hypertrophy of the future liver remnant using a mini-pig model. Ann Surg, 2008, 247(5): 825-834.
6.	Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg, 2012, 255(3): 405-414.
7.	王志明, 陶一明, 黄云, 等. 联合肝脏离断和门静脉切断二步肝切除术在肝炎后肝硬化肝癌中的应用. 中国普通外科杂志, 2014, 23(7): 867-872.
8.	刘允怡, 刘晓欣. 对“联合肝脏离断和门静脉结扎的二步肝切除术”的述评. 中华消化外科杂志, 2013, 12(7): 481-484.
9.	Schadde E, Ardiles V, Slankamenac K, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional-staged hepatectomies: results of a multicenter analysis. World J Surg, 2014, 38(6): 1510-1519.
10.	Schadde E, Ardiles V, Robles-Campos R, et al. Early survival and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg, 2014, 260(5): 829-836.
11.	Huch M, Dorrell C, Boj SF, et al. In vitro expansion of single Lgr5⁺ liver stem cells induced by Wnt-driven regeneration. Nature, 2013, 494(7436): 247-250.
12.	Leushacke M, Tan SH, Wong A, et al. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol, 2017, 19(7): 774-786.
13.	Yao L, Li C, Ge X, et al. Establishment of a rat model of portal vein ligation combined with in situ splitting. PLoS One, 2014, 9(8): e105511.
14.	Earl TM, Chapman WC. Conventional surgical treatment of hepatocellular carcinoma. Clin Liver Dis, 2011, 15(2): 353-370.
15.	郭之野. 中晚期肝细胞肝癌的靶向治疗: 困境与希望. 中国普通外科杂志, 2017, 26(1): 109-115.
16.	Kokudo N, Tada K, Seki M, et al. Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization. Hepatology, 2001, 34(2): 267-272.
17.	de Santibañes E, Clavien PA. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann Surg, 2012, 255(3): 415-417.
18.	林为东. ALPPS 促进剩余肝脏快速增生机制及相关因素研究进展. 中国普通外科杂志, 2017, 26(8): 1065-1070.
19.	段睿男, 王瑞峰. ALPPS 术后残余肝脏的再生和 CD31 的表达变化的研究. 哈尔滨医科大学学报, 2019, 53(6): 580-583.
20.	Zhao L, Dai C, Gong Q. Changes of Endocan and its effect on hepatic stem cells during the rapid proliferation process of residual liver after ALPPS procedure. Cell Biochem Funct, 2020, 38(6): 817-825.
21.	Tomassini F, D’Asseler Y, Giglio MC, et al. Hemodynamic changes in ALPPS influence liver regeneration and function: Results from a prospective study. HPB (Oxford), 2019, 21(5): 557-565.
22.	McDonald T, Wang R, Bailey W, et al. Identification and cloning of an orphan G protein-coupled receptor of the glycoprotein hormone receptor subfamily. Biochem Biophys Res Commun, 1998, 247(2): 266-270.
23.	Kumar KK, Burgess AW, Gulbis JM. Structure and function of LGR5: an enigmatic G-protein coupled receptor marking stem cells. Protein Sci, 2014, 23(5): 551-565.
24.	Plaks V, Brenot A, Lawson DA, et al. Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Rep, 2013, 3(1): 70-78.
25.	Shimokawa M, Ohta Y, Nishikori S, et al. Visualization and targeting of LGR5⁺ human colon cancer stem cells. Nature, 2017, 545(7653): 187-192.
26.	de Sousa e Melo F, Kurtova AV, Harnoss JM, et al. A distinct role for Lgr5⁺ stem cells in primary and metastatic colon cancer. Nature, 2017, 543(7647): 676-680.
27.	Lin Y, Fang ZP, Liu HJ, et al. HGF/R-spondin1 rescues liver dysfunction through the induction of Lgr5⁺ liver stem cells. Nat Commun, 2017, 8(1): 1175.
28.	Schneeberger K, Sánchez-Romero N, Ye S, et al. Large-scale production of LGR5-positive bipotential human liver stem cells. Hepatology, 2020, 72(1): 257-270.
29.	Brown DC, Gatter KC. Monoclonal antibody Ki-67: its use in histopathology. Histopathology, 1990, 17(6): 489-503.
30.	Gerlach C, Sakkab DY, Scholzen T, et al. Ki-67 expression during rat liver regeneration after partial hepatectomy. Hepatology, 1997, 26(3): 573-578.
31.	Kuijk EW, Rasmussen S, Blokzijl F, et al. Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure. Sci Rep, 2016, 6: 22154.
32.	刘伟伟, 余锋, 刘洪, 等. 大鼠 ALPPS 术后残肝再生与 Wnt2 蛋白表达关系的研究. 安徽医科大学学报, 2017, 52(9): 1331-1335.

1. Fonseca AL, Cha CH. Hepatocellular carcinoma: a comprehensive overview of surgical therapy. J Surg Oncol, 2014, 110(6): 712-719.
2. Clark ME, Smith RR. Liver-directed therapies in metastatic colorectal cancer. J Gastrointest Oncol, 2014, 5(5): 374-387.
3. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: A preliminary report. Surgery, 1990, 107(5): 521-527.
4. van den Esschert JW, van Lienden KP, Alles LK, et al. Liver regeneration after portal vein embolization using absorbable and permanent embolization materials in a rabbit model. Ann Surg, 2012, 255(2): 311-318.
5. Wilms C, Mueller L, Lenk C, et al. Comparative study of portal vein embolization versus portal vein ligation for induction of hypertrophy of the future liver remnant using a mini-pig model. Ann Surg, 2008, 247(5): 825-834.
6. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg, 2012, 255(3): 405-414.
7. 王志明, 陶一明, 黄云, 等. 联合肝脏离断和门静脉切断二步肝切除术在肝炎后肝硬化肝癌中的应用. 中国普通外科杂志, 2014, 23(7): 867-872.
8. 刘允怡, 刘晓欣. 对“联合肝脏离断和门静脉结扎的二步肝切除术”的述评. 中华消化外科杂志, 2013, 12(7): 481-484.
9. Schadde E, Ardiles V, Slankamenac K, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional-staged hepatectomies: results of a multicenter analysis. World J Surg, 2014, 38(6): 1510-1519.
10. Schadde E, Ardiles V, Robles-Campos R, et al. Early survival and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg, 2014, 260(5): 829-836.
11. Huch M, Dorrell C, Boj SF, et al. In vitro expansion of single Lgr5⁺ liver stem cells induced by Wnt-driven regeneration. Nature, 2013, 494(7436): 247-250.
12. Leushacke M, Tan SH, Wong A, et al. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol, 2017, 19(7): 774-786.
13. Yao L, Li C, Ge X, et al. Establishment of a rat model of portal vein ligation combined with in situ splitting. PLoS One, 2014, 9(8): e105511.
14. Earl TM, Chapman WC. Conventional surgical treatment of hepatocellular carcinoma. Clin Liver Dis, 2011, 15(2): 353-370.
15. 郭之野. 中晚期肝细胞肝癌的靶向治疗: 困境与希望. 中国普通外科杂志, 2017, 26(1): 109-115.
16. Kokudo N, Tada K, Seki M, et al. Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization. Hepatology, 2001, 34(2): 267-272.
17. de Santibañes E, Clavien PA. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann Surg, 2012, 255(3): 415-417.
18. 林为东. ALPPS 促进剩余肝脏快速增生机制及相关因素研究进展. 中国普通外科杂志, 2017, 26(8): 1065-1070.
19. 段睿男, 王瑞峰. ALPPS 术后残余肝脏的再生和 CD31 的表达变化的研究. 哈尔滨医科大学学报, 2019, 53(6): 580-583.
20. Zhao L, Dai C, Gong Q. Changes of Endocan and its effect on hepatic stem cells during the rapid proliferation process of residual liver after ALPPS procedure. Cell Biochem Funct, 2020, 38(6): 817-825.
21. Tomassini F, D’Asseler Y, Giglio MC, et al. Hemodynamic changes in ALPPS influence liver regeneration and function: Results from a prospective study. HPB (Oxford), 2019, 21(5): 557-565.
22. McDonald T, Wang R, Bailey W, et al. Identification and cloning of an orphan G protein-coupled receptor of the glycoprotein hormone receptor subfamily. Biochem Biophys Res Commun, 1998, 247(2): 266-270.
23. Kumar KK, Burgess AW, Gulbis JM. Structure and function of LGR5: an enigmatic G-protein coupled receptor marking stem cells. Protein Sci, 2014, 23(5): 551-565.
24. Plaks V, Brenot A, Lawson DA, et al. Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Rep, 2013, 3(1): 70-78.
25. Shimokawa M, Ohta Y, Nishikori S, et al. Visualization and targeting of LGR5⁺ human colon cancer stem cells. Nature, 2017, 545(7653): 187-192.
26. de Sousa e Melo F, Kurtova AV, Harnoss JM, et al. A distinct role for Lgr5⁺ stem cells in primary and metastatic colon cancer. Nature, 2017, 543(7647): 676-680.
27. Lin Y, Fang ZP, Liu HJ, et al. HGF/R-spondin1 rescues liver dysfunction through the induction of Lgr5⁺ liver stem cells. Nat Commun, 2017, 8(1): 1175.
28. Schneeberger K, Sánchez-Romero N, Ye S, et al. Large-scale production of LGR5-positive bipotential human liver stem cells. Hepatology, 2020, 72(1): 257-270.
29. Brown DC, Gatter KC. Monoclonal antibody Ki-67: its use in histopathology. Histopathology, 1990, 17(6): 489-503.
30. Gerlach C, Sakkab DY, Scholzen T, et al. Ki-67 expression during rat liver regeneration after partial hepatectomy. Hepatology, 1997, 26(3): 573-578.
31. Kuijk EW, Rasmussen S, Blokzijl F, et al. Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure. Sci Rep, 2016, 6: 22154.
32. 刘伟伟, 余锋, 刘洪, 等. 大鼠 ALPPS 术后残肝再生与 Wnt2 蛋白表达关系的研究. 安徽医科大学学报, 2017, 52(9): 1331-1335.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Study on relationship between remnant liver regeneration after ALPPS and Lgr5 protein expression in rat

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