In vivo partial cellular reprogramming enhances liver plasticity and regeneration.
In vivo partial cellular reprogramming enhances liver plasticity and regeneration.
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DOI：
10.1016/j.celrep.2022.110730
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发表时间：
2022-04-26
期刊：
影响因子：
8.8
通讯作者：
Belmonte, Juan Carlos Izpisua
中科院分区：
文献类型：
--
作者：
Hishida, Tomoaki;Yamamoto, Mako;Hishida-Nozaki, Yuriko;Shao, Changwei;Huang, Ling;Wang, Chao;Shojima, Kensaku;Xue, Yuan;Hang, Yuqing;Shokhirev, Maxim;Memczak, Sebastian;Sahu, Sanjeeb Kumar;Hatanaka, Fumiyuki;Ros, Ruben Rabadan;Maxwell, Matthew B.;Chavez, Jasmine;Shao, Yanjiao;Liao, Hsin-Kai;Martinez-Redondo, Paloma;Guillen-Guillen, Isabel;Hernandez-Benitez, Reyna;Esteban, Concepcion Rodriguez;Qu, Jing;Holmes, Michael C.;Yi, Fei;Hickey, Raymond D.;Guillen Garcia, Pedro;Nunez Delicado, Estrella;Castells, Antoni;Campistol, Josep M.;Yu, Yang;Hargreaves, Diana C.;Asai, Akihiro;Reddy, Pradeep;Liu, Guang-Hui;Belmonte, Juan Carlos Izpisua
哺乳动物的再生能力有限，而一些脊椎动物，如鱼和火蜥蜴，能够有效地再生它们的器官。这些物种的再生依赖于细胞的去分化和增殖。我们建立了一个小鼠模型，使四个Yamanaka因子(Oct-3/4，Sox2，Klf4和c-Myc，或4F)能够在肝细胞中特异性地诱导表达。在体内瞬时表达4F可诱导成年肝细胞部分重编程至祖细胞状态，并伴随增加细胞增殖。这表现为分化的肝脏谱系标记物的表达减少，增殖标记物和染色质修饰物的标记物增加，DNA可及性的全球变化，以及肝干细胞和祖细胞标记物的获得。在功能上，4F的短期表达通过拓扑异构酶2介导的部分重编程增强了肝脏的再生能力。我们的结果表明，肝脏特异性4F在体内的表达诱导细胞可塑性并抵消肝功能衰竭，这表明部分重编程可能是促进组织再生的一种途径。在鱼类和火蜥蜴等再生动物中，去分化和增殖有助于组织再生。Hishida等人。研究表明，肝细胞特异性细胞重编程通过拓扑异构酶2介导的部分重编程诱导肝脏细胞增殖和去分化，并增强肝脏再生能力。
Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient in vivo 4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression in vivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration. In regenerating animals, such as fish and salamanders, dedifferentiation followed by proliferation contributes to tissue regeneration. Hishida et al. show that hepatocyte-specific cellular reprogramming induces cell proliferation and dedifferentiation in the liver and enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
64.8
作者：
Abad, Maria;Mosteiro, Lluc;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
64.8
作者：
Lu Y;Brommer B;Tian X;Krishnan A;Meer M;Wang C;Vera DL;Zeng Q;Yu D;Bonkowski MS;Yang JH;Zhou S;Hoffmann EM;Karg MM;Schultz MB;Kane AE;Davidsohn N;Korobkina E;Chwalek K;Rajman LA;Church GM;Hochedlinger K;Gladyshev VN;Horvath S;Levine ME;Gregory-Ksander MS;Ksander BR;He Z;Sinclair DA
通讯作者：
Sinclair DA
影响因子：
2.7
作者：
Jin, Lin;Long, Lingyun;Spear, Brett T.
通讯作者：
Spear, Brett T.
DOI：
10.1073/pnas.96.26.15143
发表时间：
1999-12-21
影响因子：
11.1
作者：
Bezerra, JA;Bugge, TH;Degen, JL
通讯作者：
Degen, JL