Small molecule drugs promote repopulation of transplanted hepatocytes by stimulating cell dedifferentiation.
Small molecule drugs promote repopulation of transplanted hepatocytes by stimulating cell dedifferentiation.
复制标题
小分子药物通过刺激细胞去分化来促进移植肝细胞的再生。
DOI：
10.1016/j.jhepr.2023.100670
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发表时间：
2023-04
期刊：
影响因子：
8.3
通讯作者：
Xie, Xin
中科院分区：
文献类型：
--
作者：
Jiang, Mengmeng;Guo, Ren;Ai, Yan;Wang, Gang;Tang, Peilan;Jia, Xiaohui;He, Bingqing;Yuan, Qianting;Xie, Xin
关键词：
肝细胞移植已成为终末期肝病的一种可能的治疗选择。然而，治疗成功的一个重要障碍是移植肝细胞的植入和增殖水平较低，其存活时间不足以发挥治疗效果。因此，我们的目的是探索体内肝细胞增殖的机制，并找到促进移植肝细胞生长的方法。在 Fah-/- 小鼠中进行肝细胞移植，以探索体内肝细胞增殖的机制。在体内再生机制的指导下，我们鉴定出了在体外促进肝细胞增殖的化合物。然后评估这些化合物对移植肝细胞的体内影响。研究发现，移植的成熟肝细胞去分化为肝祖细胞（HPC），肝祖细胞增殖，然后在肝脏再生完成时转回成熟状态。两种小分子 Y-27632（Y，ROCK 抑制剂）和 CHIR99021（C，Wnt 激动剂）的组合可以将小鼠原代肝细胞转化为 HPC，并可在体外传代 30 次以上。此外，YC 可以通过促进 Fah-/- 肝脏中移植肝细胞转化为 HPC 来刺激其增殖。 Netarsudil (N) 和 LY2090314 (L) 是两种临床使用的药物，其靶点与 YC 相同，也可以通过促进 HPC 转化来促进体外和体内肝细胞增殖。我们的工作表明，促进肝细胞去分化的药物可能会促进移植肝细胞在体内的生长，并可能促进肝细胞治疗的应用。肝细胞移植可能是终末期肝病患者的一种治疗选择。然而，肝细胞治疗的一个重要障碍是移植肝细胞的植入和增殖水平低。在此，我们表明，通过促进去分化来促进体外肝细胞增殖的小分子化合物可以促进体内移植肝细胞的生长，并可能促进肝细胞治疗的应用。移植的肝细胞在重新增殖之前会去分化为 HPC。 Y-27632 (Y) 和 CHIR99021 (C) 将小鼠肝细胞转化为 HPC，并支持体外长期培养（> 30 代）。 YC 通过促进 Fah-/- 肝脏中移植肝细胞转化为 HPC 来刺激其增殖。两种临床使用的药物靶向与 YC 相同的途径，也在体外和体内促进肝细胞增殖。
Hepatocyte transplantation has emerged as a possible treatment option for end-stage liver disease. However, an important obstacle to therapeutic success is the low level of engraftment and proliferation of transplanted hepatocytes, which do not survive long enough to exert therapeutic effects. Thus, we aimed to explore the mechanisms of hepatocyte proliferation in vivo and find a way to promote the growth of transplanted hepatocytes. Hepatocyte transplantation was performed in Fah-/- mice to explore the mechanisms of hepatocyte proliferation in vivo. Guided by in vivo regeneration mechanisms, we identified compounds that promote hepatocyte proliferation in vitro. The in vivo effects of these compounds on transplanted hepatocytes were then evaluated. The transplanted mature hepatocytes were found to dedifferentiate into hepatic progenitor cells (HPCs), which proliferate and then convert back to a mature state at the completion of liver repopulation. The combination of two small molecules Y-27632 (Y, ROCK inhibitor) and CHIR99021 (C, Wnt agonist) could convert mouse primary hepatocytes into HPCs, which could be passaged for more than 30 passages in vitro. Moreover, YC could stimulate the proliferation of transplanted hepatocytes in Fah-/- livers by promoting their conversion into HPCs. Netarsudil (N) and LY2090314 (L), two clinically used drugs which target the same pathways as YC, could also promote hepatocyte proliferation in vitro and in vivo, by facilitating HPC conversion. Our work suggests drugs promoting hepatocyte dedifferentiation may facilitate the growth of transplanted hepatocytes in vivo and may facilitate the application of hepatocyte therapy. Hepatocyte transplantation may be a treatment option for patients with end-stage liver disease. However, one important obstacle to hepatocyte therapy is the low level of engraftment and proliferation of the transplanted hepatocytes. Herein, we show that small molecule compounds which promote hepatocyte proliferation in vitro by facilitating dedifferentiation, could promote the growth of transplanted hepatocytes in vivo and may facilitate the application of hepatocyte therapy. Transplanted hepatocytes dedifferentiate into HPCs before repopulation. Y-27632 (Y) and CHIR99021 (C) convert mouse hepatocytes into HPCs & support long-term culture (>30 passages) in vitro. YC stimulate the proliferation of transplanted hepatocytes in Fah-/- livers by promoting their conversion into HPCs. Two clinically used drugs target the same pathways as YC, also promoting hepatocyte proliferation in vitro and in vivo.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
通讯作者：
Itzkovitz S
影响因子：
64.8
作者：
通讯作者：
--
化学混合物能够利用单一转录因子对小鼠成纤维细胞进行肝脏重编程
影响因子：
5.9
作者：
Guo R;Tang W;Yuan Q;Hui L;Wang X;Xie X
通讯作者：
Xie X
影响因子：
8
作者：
Chen, Tianyi;Oh, Sehhoon;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae
影响因子：
25.7
作者：
Asrani, Sumeet K.;Devarbhavi, Harshad;Kamath, Patrick S.
通讯作者：
Kamath, Patrick S.