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Pharmacological Reprogramming of Somatic Cells for Regenerative Medicine
Accounts of Chemical Research ( IF 16.4 ) Pub Date : 2017-04-28 00:00:00 , DOI: 10.1021/acs.accounts.7b00020
Min Xie 1 , Shibing Tang 1 , Ke Li 1 , Sheng Ding 1
Affiliation  

Lost or damaged cells in tissues and organs can be replaced by transplanting therapeutically competent cells. This approach requires methods that effectively manipulate cellular identities and properties to generate sufficient numbers of desired cell types for transplantation. These cells can be generated by reprogramming readily available somatic cells, such as fibroblasts, into induced pluripotent stem cells (iPSCs), which can replicate indefinitely and give rise to any somatic cell type. This reprogramming can be achieved with genetic methods, such as forced expression of pluripotency-inducing transcription factors (TFs), which can be further improved, or even avoided, with pharmacological agents. We screened chemical libraries for such agents and identified small molecules that enhance TF-mediated pluripotency induction in somatic cells. We also developed cocktails of small molecules that can functionally replace combinations of TFs required to induce pluripotency in mouse and human somatic cells. Importantly, we devised and established a general strategy to develop effective pharmacological cocktails for specific cellular reprogramming processes. In the search for useful small molecules, we also discovered and characterized previously unknown mechanisms pertinent to cellular reprogramming.

中文翻译:

用于再生医学的体细胞的药理学重编程

组织和器官中丢失或损坏的细胞可以通过移植具有治疗能力的细胞来代替。该方法需要有效操纵细胞身份和特性以产生足够数量的所需细胞类型用于移植的方法。这些细胞可以通过将容易获得的体细胞(例如成纤维细胞)重编程为诱导性多能干细胞(iPSC)来产生,这些细胞可以无限复制并产生任何体细胞类型。这种重编程可以通过遗传方法来实现,例如强制表达多能性诱导转录因子(TFs),而使用药理学方法可以进一步改善甚至避免这种方法。我们筛选了用于此类药物的化学文库,并鉴定了可增强TF介导的体细胞多能性诱导的小分子。我们还开发了小分子混合物,可以在功能上替代在小鼠和人类体细胞中诱导多能性所需的TF组合。重要的是,我们设计并建立了总体策略,以开发针对特定细胞重编程过程的有效药理学混合物。在寻找有用的小分子时,我们还发现并表征了与细胞重编程有关的先前未知的机制。
更新日期:2017-04-28
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