Long Chunshen, Li Hanshuang, Liang Pengfei, Chao Lemuge, Hong Yan, Zhang Junping, Xi Qilemuge, Zuo Yongchun
State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China.
School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China.
Mol Ther Nucleic Acids. 2023 Oct 5;34:102044. doi: 10.1016/j.omtn.2023.102044. eCollection 2023 Dec 12.
Single-cell studies have demonstrated that somatic cell reprogramming is a continuous process of cell fates transition. Only partial reprogramming intermediates can overcome the molecular bottlenecks to acquire pluripotency. To decipher the underlying decisive factors driving cell fate, we identified induced pluripotent stem cells or stromal-like cells (iPSCs/SLCs) and iPSCs or trophoblast-like cells (iPSCs/TLCs) fate bifurcations by reconstructing cellular trajectory. The mesenchymal-epithelial transition and the activation of pluripotency networks are the main molecular series in successful reprogramming. Correspondingly, intermediates diverge into SLCs accompanied by the inhibition of cell cycle genes and the activation of extracellular matrix genes, whereas the TLCs fate is characterized by the up-regulation of placenta development genes. Combining putative gene regulatory networks, seven (, , , etc.) and three key factors (, , and ) were individually identified as drivers of the successful reprogramming by triggering downstream pluripotent networks during iPSCs/SLCs and iPSCs/TLCs fate bifurcation. Conversely, 11 factors (, , , etc.) and four factors (, , , etc.) drive SLCs fate and TLCs fate, respectively. Our study sheds new light on the understanding of decisive factors driving cell fate, which is helpful for improving reprogramming efficiency through manipulating cell fates to avoid alternative fates.
单细胞研究表明，体细胞重编程是一个细胞命运连续转变的过程。只有部分重编程中间体能够克服分子瓶颈以获得多能性。为了解析驱动细胞命运的潜在决定性因素，我们通过重建细胞轨迹确定了诱导多能干细胞或基质样细胞（iPSCs/SLCs）以及iPSCs或滋养层样细胞（iPSCs/TLCs）的命运分支。间充质-上皮转变和多能性网络的激活是成功重编程中的主要分子序列。相应地，中间体在细胞周期基因受到抑制和细胞外基质基因被激活的情况下分化为SLCs，而TLCs命运的特征是胎盘发育基因的上调。结合假定的基因调控网络，在iPSCs/SLCs和iPSCs/TLCs命运分支过程中，分别鉴定出七个（、、等）和三个关键因子（、、和）作为成功重编程的驱动因素，它们通过触发下游多能网络来实现。相反，11个因子（、、、等）和四个因子（、、、等）分别驱动SLCs命运和TLCs命运。我们的研究为理解驱动细胞命运的决定性因素提供了新的思路，这有助于通过操纵细胞命运以避免替代命运来提高重编程效率。
