Barriga Francisco M, Montagni Elisa, Mana Miyeko, Mendez-Lago Maria, Hernando-Momblona Xavier, Sevillano Marta, Guillaumet-Adkins Amy, Rodriguez-Esteban Gustavo, Buczacki Simon J A, Gut Marta, Heyn Holger, Winton Douglas J, Yilmaz Omer H, Attolini Camille Stephan-Otto, Gut Ivo, Batlle Eduard
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain.
The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA.
Cell Stem Cell. 2017 Jun 1;20(6):801-816.e7. doi: 10.1016/j.stem.2017.02.007. Epub 2017 Mar 9.
Highly proliferative Lgr5+ stem cells maintain the intestinal epithelium and are thought to be largely homogeneous. Although quiescent intestinal stem cell (ISC) populations have been described, the identity and features of such a population remain controversial. Here we report unanticipated heterogeneity within the Lgr5+ ISC pool. We found that expression of the RNA-binding protein Mex3a labels a slowly cycling subpopulation of Lgr5+ ISCs that contribute to all intestinal lineages with distinct kinetics. Single-cell transcriptome profiling revealed that Lgr5+ cells adopt two discrete states, one of which is defined by a Mex3a expression program and relatively low levels of proliferation genes. During homeostasis, Mex3a+ cells continually shift into the rapidly dividing, self-renewing ISC pool. Chemotherapy and radiation preferentially target rapidly dividing Lgr5+ cells but spare the Mex3a-high/Lgr5+ population, helping to promote regeneration of the intestinal epithelium following toxic insults. Thus, Mex3a defines a reserve-like ISC population within the Lgr5+ compartment.
高度增殖的Lgr5⁺干细胞维持肠道上皮，并且被认为在很大程度上是同质的。尽管已经描述了静止的肠道干细胞（ISC）群体，但该群体的身份和特征仍存在争议。在这里，我们报告了Lgr5⁺ISC库中意想不到的异质性。我们发现RNA结合蛋白Mex3a的表达标记了Lgr5⁺ISC的一个缓慢循环亚群，该亚群以不同的动力学方式对所有肠道谱系做出贡献。单细胞转录组分析表明，Lgr5⁺细胞呈现两种离散状态，其中一种由Mex3a表达程序和相对较低水平的增殖基因定义。在稳态期间，Mex3a⁺细胞不断转变为快速分裂、自我更新的ISC库。化疗和放疗优先靶向快速分裂的Lgr5⁺细胞，但使Mex3a高表达/Lgr5⁺群体免受影响，有助于促进肠道上皮在毒性损伤后的再生。因此，Mex3a在Lgr5⁺区室中定义了一个类似储备的ISC群体。
