Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming.
Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming.
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DOI：
10.1016/j.stem.2017.10.013
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发表时间：
2017-12-07
期刊：
影响因子：
23.9
通讯作者：
Kaji K
中科院分区：
文献类型：
--
作者：
Ruetz T;Pfisterer U;Di Stefano B;Ashmore J;Beniazza M;Tian TV;Kaemena DF;Tosti L;Tan W;Manning JR;Chantzoura E;Ottosson DR;Collombet S;Johnsson A;Cohen E;Yusa K;Linnarsson S;Graf T;Parmar M;Kaji K
使用转录因子（TF）的外源表达来重编程细胞身份是组织工程、疾病建模和再生医学的强大且令人兴奋的工具。然而，使用这种方法产生所需的细胞类型通常受到效率低下、转化缓慢和不能产生成熟功能细胞的困扰。在这里，我们表明，组成型活性SMAD 2/3的表达显着提高诱导多能干细胞（iPSC）的效率，由Yamanaka因素。在机制上，SMAD 3与重编程因子和共激活因子相互作用，并在重编程期间共占据OCT 4靶基因座。出乎意料的是，活性SMAD 2/3还显著增强了其他三种TF介导的直接重编程转换，从B细胞到巨噬细胞，成肌细胞到脂肪细胞，以及人成纤维细胞到神经元，突出了SMAD 2/3作为细胞重编程增强剂的广泛和一般作用。我们的研究结果表明，活性SMAD 2/3的共表达可以增强多种类型的TF为基础的细胞身份转换，因此是一个强大的工具，细胞工程。通过TGF-βR抑制增强iPSC重编程不依赖于SMAD 2/3组成型活性SMAD 2/3提高重编程效率和动力学SMAD 3在重编程期间共占据OCT 4靶点组成型活性SMAD 2/3也增强TF介导的直接谱系重编程Ruetz et al.表明组成型活性SMAD 2/3具有令人惊讶的能力，可以提高细胞重编程为iPSC和跨谱系的效率，因此可能是在各种情况下可以增强转录因子介导的重编程的一般因素。
Reprogramming of cellular identity using exogenous expression of transcription factors (TFs) is a powerful and exciting tool for tissue engineering, disease modeling, and regenerative medicine. However, generation of desired cell types using this approach is often plagued by inefficiency, slow conversion, and an inability to produce mature functional cells. Here, we show that expression of constitutively active SMAD2/3 significantly improves the efficiency of induced pluripotent stem cell (iPSC) generation by the Yamanaka factors. Mechanistically, SMAD3 interacts with reprogramming factors and co-activators and co-occupies OCT4 target loci during reprogramming. Unexpectedly, active SMAD2/3 also markedly enhances three other TF-mediated direct reprogramming conversions, from B cells to macrophages, myoblasts to adipocytes, and human fibroblasts to neurons, highlighting broad and general roles for SMAD2/3 as cell-reprogramming potentiators. Our results suggest that co-expression of active SMAD2/3 could enhance multiple types of TF-based cell identity conversion and therefore be a powerful tool for cellular engineering. Enhancement of iPSC reprogramming by TGF-βR inhibition is independent of SMAD2/3 Constitutively active SMAD2/3 improves reprogramming efficiency and kinetics SMAD3 co-occupies OCT4 targets during reprogramming Constitutively active SMAD2/3 also boosts TF-mediated direct lineage reprogramming Ruetz et al. show that constitutively active SMAD2/3 has a surprising ability to boost the efficiency of cell reprogramming both to iPSCs and across lineages and may therefore be a general factor that can enhance transcription-factor-mediated reprogramming in a variety of contexts.
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0711961105
发表时间：
2008-04-22
影响因子：
11.1
作者：
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通讯作者：
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