The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, NY 10016, USA.
Stem Cell Reports. 2014 Oct 14;3(4):574-84. doi: 10.1016/j.stemcr.2014.08.003.
The differentiated state of somatic cells provides barriers for the derivation of induced pluripotent stem cells (iPSCs). To address why some cell types reprogram more readily than others, we studied the effect of combined modulation of cellular signaling pathways. Surprisingly, inhibition of transforming growth factor β (TGF-β) together with activation of Wnt signaling in the presence of ascorbic acid allows >80% of murine fibroblasts to acquire pluripotency after 1 week of reprogramming factor expression. In contrast, hepatic and blood progenitors predominantly required only TGF-β inhibition or canonical Wnt activation, respectively, to reprogram at efficiencies approaching 100%. Strikingly, blood progenitors reactivated endogenous pluripotency loci in a highly synchronous manner, and we demonstrate that expression of specific chromatin-modifying enzymes and reduced TGF-β/mitogen-activated protein (MAP) kinase activity are intrinsic properties associated with the unique reprogramming response of these cells. Our observations define cell-type-specific requirements for the rapid and synchronous reprogramming of somatic cells.
体细胞的分化状态为诱导多能干细胞（iPSCs）的产生设置了障碍。为了解释为什么有些细胞类型比其他细胞类型更容易重编程，我们研究了细胞信号通路联合调控的效果。令人惊讶的是，在存在抗坏血酸的情况下，抑制转化生长因子β（TGF-β）并激活 Wnt 信号通路，可使超过 80%的小鼠成纤维细胞在重编程因子表达 1 周后获得多能性。相比之下，肝和血液祖细胞主要分别只需要抑制 TGF-β 或激活经典 Wnt 就可以接近 100%的效率进行重编程。引人注目的是，血液祖细胞以高度同步的方式重新激活内源性多能性基因座，我们证明，特定染色质修饰酶的表达和 TGF-β/丝裂原活化蛋白（MAP）激酶活性的降低是与这些细胞独特的重编程反应相关的固有特性。我们的观察结果定义了体细胞快速和同步重编程的细胞类型特异性要求。
