Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
The National Center for Biotechnology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
Mol Cell Biol. 2020 Apr 13;40(9). doi: 10.1128/MCB.00508-19.
During aging, cellular plasticity and senescence play important roles in tissue regeneration and the pathogenesis of different diseases, including cancer. We have recently shown that senescent breast luminal cells can activate their adjacent stromal fibroblasts. In the present report, we present clear evidence that these senescence-related active fibroblasts can dedifferentiate proliferating primary human luminal cells to multipotent stem cells in an interleukin-8 (IL-8)-dependent manner. This was confirmed using recombinant IL-8, while the truncated protein was not active. This IL-8-related dedifferentiation of luminal cells was mediated through the STAT3-dependent downregulation of p16 and the microRNA miR-141. Importantly, these -generated mammary stem cells exhibited high molecular and cellular similarities to human mammary stem cells. They have also shown a long-term mammary gland-reconstituting ability and the capacity to produce milk postdelivery. Thereby, these IL-8-generated mammary stem cells could be of great value for autologous cell therapy procedures and also for biomedical research as well as drug development.
在衰老过程中，细胞可塑性和衰老在组织再生和包括癌症在内的不同疾病的发病机制中起着重要作用。我们最近表明，衰老的乳腺腔细胞可以激活其相邻的基质成纤维细胞。在本报告中，我们提供了明确的证据表明，这些与衰老相关的活跃成纤维细胞可以通过白细胞介素-8（IL-8）依赖性方式将增殖的原代人乳腺腔细胞去分化为多能干细胞。这是通过使用重组 IL-8 来证实的，而截短的蛋白质没有活性。这种 IL-8 相关的腔细胞去分化是通过 STAT3 依赖性下调 p16 和 microRNA miR-141 来介导的。重要的是，这些产生的乳腺干细胞表现出与人乳腺干细胞高度相似的分子和细胞特征。它们还显示出长期的乳腺重建能力和产后产奶能力。因此，这些 IL-8 产生的乳腺干细胞在自体细胞治疗程序以及生物医学研究和药物开发方面可能具有很高的价值。
