小柯机器人

澳大利亚莫纳什大学Jose M. Polo研究团队利用重编程路线图揭示了人类诱导滋养层干细胞的生成途径。该项研究成果在线发表在2020年9月16日的《自然》上。

在本研究中，为了解决重编程分子机制的问题，研究人员利用单细胞转录组学重现了人皮肤成纤维细胞的分子重编程轨迹。研究表明，重编程为初始和原始多能干细胞遵循着截然不同的轨迹。

此外,可及染色质全基因组分析表明核心多能性基因调控元件的关键变化，以及随着时间的推移，染色质可及性的整体变化。对这些数据集的综合分析揭示了与滋养外胚层谱系相关的转录因子功能，以及在重编程过程中进入滋养外胚层样细胞亚群的存在。

并且，这种类似于滋养外胚层的状态可以被观察到，并能够诱导滋养层干细胞。诱导的滋养层干细胞在分子和功能上类似于人胚泡或早孕胎盘的滋养层干细胞。该研究结果为转录因子介导的人体细胞重编程提供了高分辨率路线图，表明了滋养外胚层谱系特异性调控程序在此过程中的作用，并促进了体细胞直接重编程为诱导滋养层干细胞的发展。

研究人员表示，人体细胞重编程为初始或原始诱导多能干细胞，重现了早期胚胎发育的阶段。在很大程度上这些重编程过程的分子机制尚未揭示，这阻碍了人们的理解，并限制了对重编程方案的合理改进。

附：英文原文

Title: Reprogramming roadmap reveals route to human induced trophoblast stem cells

Author: Xiaodong Liu, John F. Ouyang, Fernando J. Rossello, Jia Ping Tan, Kathryn C. Davidson, Daniela S. Valdes, Jan Schrder, Yu B. Y. Sun, Joseph Chen, Anja S. Knaupp, Guizhi Sun, Hun S. Chy, Ziyi Huang, Jahnvi Pflueger, Jaber Firas, Vincent Tano, Sam Buckberry, Jacob M. Paynter, Michael R. Larcombe, Daniel Poppe, Xin Yi Choo, Carmel M. OBrien, William A. Pastor, Di Chen, Anna L. Leichter, Haroon Naeem, Pratibha Tripathi, Partha P. Das, Alexandra Grubman, David R. Powell, Andrew L. Laslett, Laurent David, Susan K. Nilsson, Amander T. Clark, Ryan Lister, Christian M. Nefzger, Luciano G. Martelotto, Owen J. L. Rackham, Jose M. Polo

Issue&Volume: 2020-09-16

Abstract: The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development1,2,3,4,5,6. The molecular mechanism that underpins these reprogramming processes remains largely unexplored, which impedes our understanding and limits rational improvements to reprogramming protocols. Here, to address these issues, we reconstruct molecular reprogramming trajectories of human dermal fibroblasts using single-cell transcriptomics. This revealed that reprogramming into primed and naive pluripotency follows diverging and distinct trajectories. Moreover, genome-wide analyses of accessible chromatin showed key changes in the regulatory elements of core pluripotency genes, and orchestrated global changes in chromatin accessibility over time. Integrated analysis of these datasets revealed a role for transcription factors associated with the trophectoderm lineage, and the existence of a subpopulation of cells that enter a trophectoderm-like state during reprogramming. Furthermore, this trophectoderm-like state could be captured, which enabled the derivation of induced trophoblast stem cells. Induced trophoblast stem cells are molecularly and functionally similar to trophoblast stem cells derived from human blastocysts or first-trimester placentas7. Our results provide a high-resolution roadmap for the transcription-factor-mediated reprogramming of human somatic cells, indicate a role for the trophectoderm-lineage-specific regulatory program during this process, and facilitate the direct reprogramming of somatic cells into induced trophoblast stem cells.

DOI: 10.1038/s41586-020-2734-6

Source: https://www.nature.com/articles/s41586-020-2734-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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