Vallmajo-Martin Queralt, Ma Zhibo, Srinivasan Sumana, Murali Divya, Dravis Christopher, Mukund Kavitha, Subramaniam Shankar, Wahl Geoffrey M, Lytle Nikki K
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
These authors contributed equally.
bioRxiv. 2024 Nov 4:2024.10.08.617155. doi: 10.1101/2024.10.08.617155.
The adult mammary gland is maintained by lineage-restricted progenitor cells through pregnancy, lactation, involution, and menopause. Injury resolution, transplantation-associated mammary gland reconstitution, and tumorigenesis are unique exceptions, wherein mammary basal cells gain the ability to reprogram to a luminal state. Here, we leverage newly developed cell-identity reporter mouse strains, and time-resolved single-cell epigenetic and transcriptomic analyses to decipher the molecular programs underlying basal-to-luminal fate switching . We demonstrate that basal cells rapidly reprogram toward plastic cycling intermediates that appear to hijack molecular programs we find in bipotent fetal mammary stem cells and puberty-associatiated cap cells. Loss of basal-cell specifiers early in dedifferentiation coincides with activation of Notch and BMP, among others. Pharmacologic blockade of each pathway disrupts basal-to-luminal transdifferentiation. Our studies provide a comprehensive map and resource for understanding the coordinated molecular changes enabling terminally differentiated epithelial cells to transition between cell lineages and highlights the stunning rapidity by which epigenetic reprogramming can occur in response to disruption of tissue structure.
成年乳腺在整个怀孕、哺乳、退化和绝经过程中由谱系受限的祖细胞维持。损伤修复、移植相关的乳腺重建和肿瘤发生是独特的例外情况，在此过程中乳腺基底细胞获得重编程为管腔状态的能力。在这里，我们利用新开发的细胞身份报告基因小鼠品系，以及时间分辨的单细胞表观遗传和转录组分析，来破译基底细胞向管腔命运转变的分子程序。我们证明，基底细胞迅速重编程为可塑性循环中间体，这些中间体似乎劫持了我们在双能胎儿乳腺干细胞和青春期相关帽细胞中发现的分子程序。去分化早期基底细胞特异性因子的丧失与Notch和BMP等的激活同时发生。对每条途径的药理学阻断都会破坏基底细胞向管腔细胞的转分化。我们的研究提供了一个全面的图谱和资源，用于理解使终末分化上皮细胞能够在细胞谱系之间转变的协调分子变化，并突出了表观遗传重编程响应组织结构破坏而发生的惊人速度。
