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哺乳动物发育和癌前期的时间记录

Mirazul Islam ^1,2, Yilin Yang ^1,2, Alan J Simmons ^1,2

¹Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
²Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
³Department of Computer Science and Engineering, Indian Institute of Technology Kanpur, Kanpur, India.
⁴Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN, USA.
⁵Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA.
⁶Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁹Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
¹¹Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹²Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹³Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, India.
¹⁴Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁶Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
¹⁷Department of Medicine, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁸Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁹Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA. robert.coffey@vumc.org.
²⁰Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. robert.coffey@vumc.org.
²¹Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA. robert.coffey@vumc.org.
²²Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. robert.coffey@vumc.org.
²³Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA. robert.coffey@vumc.org.
²⁴Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA. ken.s.lau@vanderbilt.edu.
²⁵Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. ken.s.lau@vanderbilt.edu.
²⁶Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN, USA. ken.s.lau@vanderbilt.edu.
²⁷Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA. ken.s.lau@vanderbilt.edu.
²⁸Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. ken.s.lau@vanderbilt.edu.
²⁹Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA. ken.s.lau@vanderbilt.edu.
³⁰Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. ken.s.lau@vanderbilt.edu.
³¹Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. ken.s.lau@vanderbilt.edu.

⁰Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Nature +

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2024年十月31日

在PubMed上查看摘要

概括

研究人员开发了一种基于CRISPR的分子时钟,以追踪体内细胞事件和克隆性. 这种方法精确地定时胚胎发育,并揭示了15-30%的人类结肠癌前期的多克隆起源.

科学领域

遗传学
发育生物学
癌症研究

背景情况

了解细胞事件的时间对于生物见解至关重要.
传统的方法依赖于直接观察, 但不可逆转的遗传变化提供了回顾性的时间排序.
需要一种新的分子时钟方法来记录细胞事件和细胞系.

研究的目的

开发一个多用途的单细胞CRISPR平台以记录细胞事件和克隆性.
整合细胞状态和血统信息与时间记录.
探索瘤发育的起源和时间.

主要方法

开发了一个单细胞CRISPR平台来创建分子时钟.
在体内记录细胞事件的时间,克隆性,细胞状态和血统.
分析了小鼠胚胎发育,小鼠腺瘤和人类癌前/多胞体,使用多细胞和单细胞分析.

主要成果

在小鼠胚胎发育过程中精确定时的组织特异性细胞扩张.
发现了非传统的发育关系和新的上皮原生态.
在15-30%的人类结肠癌前期病例中证明了多克隆启动,来源于多个创始人.

结论

使用基因变化和单细胞分析进行体内记录的多模式框架.
奠定了探索哺乳动物发育和瘤发生的起源和时间的基础.
突出了分子钟对于理解复杂的生物过程的有用性.